Fused azepine derivatives and their use as antidiuretic agents

ABSTRACT

Compounds according to general formulae (1 and 2), wherein G 1  is an azepine derivative and G 2  is a group according to general formulae (9-11) are new. Compounds according to the invention are vasopressin V 2  receptor agonists. Pharmaceutical compositions of the compounds are useful as antidiuretic agents.

FIELD OF INVENTION

[0001] The present invention relates to a class of novel chemicalentities which act as agonists of the peptide hormone vasopressin. Theyreduce urine output from the kidneys and so are useful in the treatmentof certain human diseases characterised by polyuria. They are alsouseful in the control of urinary incontinence and bleeding disorders.

BACKGROUND TO THE INVENTION

[0002] Vasopressin is a peptide hormone secreted by the posteriorpituitary gland. It acts on the kidney to increase water retention andso reduce urine output. For this reason, vasopressin is alternativelyknown as “antidiuretic hormone”. It also acts on the vasculature, whereIt produces a hypertensive effect. The cellular receptors that mediatethese two actions have been characterised and shown to be different. Theantidiuretic action is mediated by the type-2 vasopressin receptor,commonly called the V₂ receptor. Agents that can interact with the V₂receptor and activate it in the same way as vasopressin are called V₂receptor agonists (or simply V₂ agonists). Such agents will have anantidiuretic action. If these agents interact selectively with the V₂receptor and not the other vasopressin receptor subtypes, then they willnot have the hypertensive effect of vasopressin. This would be animportant safety consideration and make such agents attractive for thetreatment of human disease conditions characterised by polyuria (whichis herein taken to mean excessive urine production).

[0003] In fact, such an agent is already in use in human therapy.Desmopressin (otherwise [1-desarnino, D-Arg⁸]vasopressin, Minirin™,DDAVP™, Octostim™) is a peptide analogue of vasopressin which isselectively an agonist at the V₂ receptor. It is used in the treatmentof central diabetes insipidus, which is a condition that results fromdefective secretion of vasopressin. It is also employed in the controlof nocturnal enuresis and may also be of use in the control of nocturia.However, desmopressin is not an ideal agent in all respects. Even thebest current syntheses of the agent are lengthy, and desmopressin is notamenable to the most convenient of purification techniques such ascrystallisation. Consequently, desmopressin is relatively expensive. Ithas a very low oral bioavailability, and there is some variability inthis parameter.

[0004] Overall then, there is a recognised need for a selectivevasopressin V₂ receptor agonist that is easy to prepare and purify, andthat has a high and predictable oral bioavailability. Such propertiesare most likely to be obtained with a non-peptide compound. Examples ofsuch compounds are disclosed by Ogawa et al. in International PatentApplication PCT/JP96/03652 (WO97/22591), by Failli et al. inPCT/US98/15487 (WO99/06403), PCT/US00/00885 (WO00/46224), andPCT/US00/00358 (WO00/46227), by Dusza et al. in PCT/US98/15495(WO99/06409), and by Steffan and Failli in PCT/US00/00886 (WO00/46225),and PCT/US00/00658 (WO00/46228). However the compounds disclosed inthese documents are not ideal drug candidates. For example, some haveonly moderate selectivity for the V₂ receptor and many have only verylimited oral bioavailability, probably because they are poorly solublein aqueous media. The present invention provides compounds that show abetter combination of properties.

[0005] The anti-diuretic action of desmopressin results in a d crease inthe osmolarity of the blood, and this has been shown to be useful in thtreatment and prophylaxis of sickle-cell disease. Besides itsantidiuretic actions, desmopressin is used to increase the concentrationin the blood of the coagulation proteins known as Faktor VIII and vonWillebrand factor In the clinical context, this makes desmopressinuseful in the treatment of haemophilia A and von Willebrand's disease.Desmopressin has also been reported to show effects in the centralnervous system. For example, it has been reported to be effective in thetreatment of Tourette's disease and to be useful in the management ofcocaine addiction. Similar applications would be open to the non-peptideagonists of the present invention.

SUMMARY OF THE INVENTION

[0006] The present invention relates to a series of compounds accordingto general formulae 1 and 2, and to salts and tautomers thereof, thatare non-peptide agonists of vasopressin and which are selective for theV₂ receptor subtype.

[0007] wherein:

[0008] W is either N or C—R⁴;

[0009] R¹-R⁴ are independently selected from H, F, Cl, Br, alkyl, CF₃,phenyl, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂, NO₂ and CN, or R² and R³together can be —CH═CH—CH═CH—;

[0010] G¹ is a bicyclic or tricyclic fused azepine derivative selectedfrom general formulae 3 to 8,

[0011]  in which A¹, A⁴, A⁷ and A¹⁰ are each independently selected fromCH₂, O and NR⁵;

[0012] A², A³, A⁹, A¹¹, A¹³, A¹⁴ and A¹⁵ are each independently selectedfrom CH and N;

[0013] either A⁵ is a covalent bond and A⁶ is S, or A⁵ is N═CH and A⁶ isa covalent bond;

[0014] A⁸ and A¹² are each independently selected from NH, N—CH₃ and S;

[0015] A¹⁶ and A¹⁷ are both CH₂, or one of A¹⁶ and A¹⁷ is CH₂ and theother is selected from CH(OH), CF₂, O, SO_(a) and NR⁵;

[0016] R⁵ is selected from H, alkyl and (CH₂)_(b)R⁶;

[0017] R⁶ is selected from phenyl, pyridyl, OH, O-alkyl, NH₂, NH-alkyl,N(alkyl)₂, NO₂, CO₂H and CN;

[0018] a is 0, 1 or 2;

[0019] b is 1, 2, 3 or 4;

[0020] Y is CH or N;

[0021] Z is CH═CH or S; and

[0022] G² is a group selected from general formulae 9 to 11,

[0023]  in which Ar is selected from phenyl, pyridyl, naphthyl and mono-or polysubstituted phenyl or pyridyl wherein the substituents areselected from F, Cl, Br, alkyl, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂,NO₂ and CN;

[0024] D is a covalent bond or NH;

[0025] E¹ and E² are both H, OMe or F, or one of E¹ and E² is OH,O-alkyl, OBn, OPh, OAc, F, Cl, Br, N₃, NH₂, NHBn or NHAc and the otheris H, or E¹ and E² together are ═O, —O(CH₂)_(g)O— or —S(CH₂)_(g)S—;

[0026] F¹ and F² are both H, or together are ═O or ═S;

[0027] L is selected from OH, O-alkyl, NH₂, NH-alkyl and NR⁹R¹⁰;

[0028] R⁷ is selected from H, alkyl, alkenyl and COR⁸;

[0029] R⁸ is selected from OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂,pyrrolidinyl and piperidinyl;

[0030] R⁹ and R¹⁰ are both alkyl, or together are —(CH₂)_(h)— or—(CH₂)₂O(CH₂)₂—;

[0031] V is O, N—CN or S;

[0032] c is 0 or 1;

[0033] d is 0 or 1;

[0034] e is 0 or 1;

[0035] f is 0, 1, 2, 3 or 4;

[0036] g is 2 or 3; and

[0037] h is 3,4 or 5,

[0038] provided that d and e are not both 0.

[0039] The invention further comprises pharmaceutical compositionsincorporating these vasopressin agonists, which compositions areparticularly useful in the treatment of central diabetes insipidus,nocturnal enuresis and nocturia.

DESCRIPTION OF THE INVENTION

[0040] In a first aspect, the present invention comprises novel4-(aminomethyl)benzamide and 6(aminomethyl)nicotinamide derivativesaccording to general formulae 1 and 2.

[0041] In general formula 1, W represents either a nitrogen atom (N) ora substituted carbon atom (C—R⁴). The substituents R¹-R⁴ are eachindependently selected from hydrogen (H), fluorine (F), chlorine (Cl)and bromine (Br) atoms, and alkyl, trifluoromethyl (CF₃), phenyl (Ph),hydroxyl (OH), alkoxy (O-alkyl), primary amino (NH₂), monoalkylamino(NH-alkyl), dialkylamino (N(alkyl)₂), nitro (NO₂) and cyano (CN) groups.Altematively, R² and R³ together can be —CH═CH—CH═CH— such that togetherwith the ring to which they are attached they form a naphthalene,isoquinoline or isoquinolin-3one fused ring system. The relationshipbetween the two general formulae above is clear when one considers thecompound of general formula 1 in which W is nitrogen and R¹ is hydroxyl.The resulting 2-hydroxypyridine can also exist as its 2-pyridonetautomer. In this tautomeric form the nitrogen atom is able to carry asubstituent equivalent to R⁴, and such a compound is represented bygeneral formula 2.

[0042] The group G¹ is a bicyclic or tricyclic fused azepine derivativeselected from general formulae 3 to 8. It is joined to the carbonylgroup of the parent molecule (1 or 2) through the nitrogen atom of theazepine ring common to all of 3 to 8, so as to form an amide bond.

[0043] In these formulae, A¹, A⁴, A⁷ and A¹⁰ each represent an oxygenatom (—O—) or a methylene (—CH₂—) or substituted imino (—NR⁵—) group.A², A³, A⁹, A¹¹, A¹³, A¹⁴ and A¹⁵ each represent a methine group (═CH—)or a nitrogen atom (═N—). Where two or more of these occur in the samegroup, each is independent of the others. Thus, for example, in formula3, A² and A³ may both be nitrogen, both methine, or one may be methineand the other nitrogen. A⁵ and A⁶ are chosen together such that eitherA⁵ is a covalent bond and A⁶ is a sulphur atom (—S—), to give athiophene ring, or A⁵ is a group —N═CH— and A⁶ is a covalent bond togive a pyridine ring. A⁸ and A¹² each represent an imino group (—NH—),an N-methyl imino group (—NCH₃—) or a sulphur atom (—S—). A¹⁶ and A¹⁷may both represent a methylene group (—CH₂—) or one of A¹⁶ and A¹⁷ mayrepresent a methylene group while the other represents ahydroxymethylene group (—CH(OH)—), a difluoromethylene group (—CF₂—), asubstituted imino group (—NR⁵—), an oxygen atom (—O—), or an optionallyoxidised sulphur atom (—SO_(a)—), where a is zero, 1 or 2.

[0044] The group R⁵ represents a hydrogen atom (H), an alkyl group, or agroup —(CH₂)_(b)R⁶, where b is 1, 2, 3 or 4. The group R⁶ represents agroup selected from phenyl, pyridyl, hydroxy (—OH), alkoxy (—O-alkyl),primary amino (—NH₂), mono- and dialkylamino (—NH-alkyl and N(alkyl)₂),nitro (—NO₂), carboxy (—CO₂H) and cyano (—CN) groups.

[0045] Y represents either a methine group (═CH—) or a nitrogen atom(═N—). Z represents either a sulphur atom (—S—) or a group —CH═CH—.

[0046] The group G² is selected from general formulae 9 to 11.

[0047] In these formulae, V represents a divalent residue selected fromoxygen (═O) and sulphur (═S) atoms and a cyanimide (═N—CN) group.

[0048] In general formula 9, Ar represents an aromatic group selectedfrom phenyl, pyridyl, naphthyl and mono— or polysubstituted phenyl andpyrdyl groups, wherein the substituents are selected from fluorine (F),chlorine (Cl) and bromine (Br) atoms and alkyl, hydroxy (—OH), alkoxy(—O-alkyl), primary amino (—NH₂), mono- and dialkylamino (—NH-alkyl andN(alkyl)₂), nitro (—NO₂), carboxy (—CO₂H) and cyano (—CN) groups. Thevalues of c, d and e are independently zero or 1, provided that d and eare not both zero.

[0049] In general formula 10, D represents a covalent bond or an iminogroup (—NH—). The group R⁷ represents a hydrogen atom (H), an alkyl oralkenyl group, or a group —COR⁸, in which R⁸ represents a hydroxy (—OH),alkoxy (—O-alkyl), primary amino (—NH₂) or mono- or dialkylamino(—NH-alkyl and N(alkyl)₂) group, or a cyclic amino group selected frompyrrolidinyl (—N(CH₂)₄) and piperidinyl (—N(CH₂)₅). The value of f iszero, 1, 2, 3 or 4.

[0050] In general formula 11, E¹ and E² represent either two monovalentatoms or groups, which may be the same or different, or together theyrepresent a divalent atom or group. When E¹ and E² represent monovalentatoms or groups, these may both simultaneously be hydrogen (H) orfluorine (F) atoms or methoxy (—OMe) groups, or one may be a fluorine(F), chlorine (Cl) or bromine (Br) atom, or a hydroxy (—OH), alkoxy(—O-alkyl), benzyloxy (—OBn), phenoxy (—OPh), acetoxy (—OAc), azido(—N₃), primary amino (—NH₂), benzylamino (—NHBn) or acetamido (—NHAc)group and the other is a hydrogen atom (H). When E¹ and E² togetherrepresent a divalent atom or group, this may be an oxygen atom (═O) oran α,ω-dioxa- or dithiapolymethylene group (—O(CH₂)_(g)O— or—S(CH₂)_(g)S—), in which the value of g is either 2 or 3.

[0051] F¹ and F² may both represent a hydrogen (H) atom. Altematively,they may together represent an oxygen (═O) or sulphur (═S) atom. Lrepresents a group selected from hydroxy (—OH), alkoxy (—O-alkyl),primary amino (—NH₂) and monoalkylamino (—NH-alkyl) groups and —NR⁹R¹⁰,wherein either R⁹ and R¹⁰ each represent alkyl groups which may be thesame or different, or together they represent a polymethylene group(—(CH₂)h—) in which h can be 3, 4 or 5, or —(CH₂)₂O(CH₂)₂—.

[0052] As used herein, the term “alkyr” includes saturated hydrocarbonresidues, including linear, branched and cyclic groups, with up to sixcarbon atoms. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, seo-butyl, isobutyl,tert-butyl, neopentyl and cyclohexyl groups.

[0053] The term “alkenyl” includes mono-unsaturated hydrocarbonresidues, including linear, branched and cyclic groups, of between twoand six carbon atoms. Examples of alkenyl groups include, but are notlimited to, vinyl, 1-propenyl, allyl, 2-methyl-2-propenyl, 2-butenyl,3-cyclopentenyl and 2,3-dimethyl-2-butenyl groups.

[0054] Certain compounds within the scope of the present invention mayexist as tautomers. For example, when W is nitrogen and R¹ or R² is ahydroxy group, or when Ar is pyridyl further substituted by a hydroxygroup, the resulting hydroxypyridine can exist as the pyridone tautomer.All such tautomers are considered to be within the scope of the presentinvention.

[0055] Certain compounds of general formula 1 are capable of formingsalts with acids or bases. For example, compounds containing one or morebasic nitrogen atoms can form addition salts with mineral and organicacids such as hydrochloric acid, sulphuric acid, phosphoric acid, aceticacid, trifluoroacetic acid, methanesulphonic acid, citric acid andbenzoic acid. Compounds containing acidic groups can form salts withbases. Examples of such salts include the sodium, potassium, calcium,triethylammonium and tetraethylammonium salts. Furthermore, compoundsthat have both acidic and basic groups can form internal salts(zwiterions). Insofar as these salts are pharmaceutically acceptable,they are included within the scope of the invention.

[0056] A preferred embodiment of the invention is a compound accordingto general formula 1. More preferred is a compound according to generalformula 1 in which W is C—R⁴. Even more preferred is such a compound inwhich at least one of R¹-R⁴ is other than hydrogen. Most preferred is acompound in which one of R¹-R⁴ is methyl, chlorine or fluorine and theother three are hydrogen.

[0057] Another preferred embodiment of the invention is a compoundaccording to general formula 2. More preferred is a compound accordingto general formula 2 in which R² and R³ are both hydrogen.

[0058] Another preferred embodiment of the invention is a compoundaccording to general formulae 1 or 2 in which G¹ is a group according toany of general formulae 3 to 7. More preferred is a compound in which Yis CH. Even more preferred is a compound in which Z is —CH═CH— so as tocomplete a benzenoid ring. Alternatively, Z may be S to complete athiophene ring. When Y is N it is particularly preferred that Z be—CH═CH— so as to complete a pyridine ring.

[0059] Within the foregoing preferred embodiment, more preferredcompounds are those wherein G¹ is a group according to general formula3, particularly those wherein A¹ is CH₂ and both A² and A³ are CH, andcompounds wherein G¹ is a group according to general formula 6,particularly those wherein A¹¹ is CH and A¹² is S.

[0060] Another preferred embodiment of the invention is a compoundaccording to general formulae 1 or 2 in which G¹ is a group according togeneral formula 8. More preferred is a compound in which one of A¹⁶ andA¹⁷ is CH₂. Even more preferred is a compound in which both A¹⁶ and A¹⁷are CH₂.

[0061] Another preferred embodiment of the invention is a compoundaccording to general formulae 1 or 2 in which G² is a group according togeneral formula 9. More preferred are those compounds wherein Ar ismono- or polysubstituted phenyl. Even more preferred are phenyl groupswith at least two halogen (fluorine or chlorine) substituents. Mostpreferably, Ar is 2,6-difluorophenyl.

[0062] Another preferred embodiment of the invention is a compoundaccording to general formulae 1 or 2 in which G² is a group according togeneral formula 10. More preferred are those compounds wherein R⁷ isCOR⁸. Most preferred are those compounds wherein R⁸ is N(alkyl)₂.

[0063] Another preferred embodiment of the invention is a compoundaccording to general formulae 1 or 2 in which G² is a group according togeneral formula 11. More preferred are those compounds wherein F¹ and F²together are ═O. Also preferred are those compounds wherein both E¹ andE² are H, or one is H and the other is O-alkyl. For those compoundswherein one of E¹ and E² is H and the other is O-alkyl, it is preferredthat the stereochemistry at the CE¹E² centre be of the R absoluteconfiguration. It is further preferred that the stereochemistry adjacentto the ring nitrogen atom be of the S absolute configuration. Theseconfigurations are illustrated below.

[0064] To the extent that the features of the foregoing preferredembodiments are independent of each other they may be combined inembodiments that are more preferred. Thus, highly preferred embodimentsof the invention are those compounds that combine the preferred optionsfor W and R¹-R⁴ with the preferred options for G¹ and G².

[0065] A most preferred embodiment of the invention is a compoundselected from the following.

[0066]1-(4-[3(2-Chloro-6-fluorophenyl)ureidomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0067]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5-(3-pyridyl)methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0068]1-(3-Chloro-4-[3-(2-chloro-6-fluorophenyl)ureidomethyl]benzoyl)-5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0069]4-(3-Chloro-4-[3-(2,6-difluorophenyl)ureidomethyl]benzoyl)-5,6,7,8-tetrahydrothieno[3,2-b]azepine

[0070]1-(3-Chloro-4-(3-(methyloxycarbonyl)propanoylaminomethyl)benzoyl)-2,3,4,5-tetrahydro-1-benzazepine

[0071]1-(2-Methyl-4-(5-(3-pyridylmethyl)-2,3,4,5-tetrahydro-1,5-benzodiazepin-1-ylcarbonyl)benzyl)-3-(methyloxycarbonylmethyl)urea

[0072]1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide

[0073](4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide

[0074](4R)-1-(3-Chloro-4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide

[0075](4R)-1-(2-Chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide

[0076](4R)-4-Benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide

[0077](4R)-4-Methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide

[0078](4R)-4-Methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide

[0079](4R)-1-(2-Chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-ylcarbonyl)benzyl-carbamoyl)-4-methoxy-L-proline-N,N-dimethylamide

[0080](4R)-1-(4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide

[0081](4R)-1-(2-Chloro-4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide

[0082](4R)-1-(4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylthioamide

[0083] Within this set of compounds, two which show an optimal balanceof properties are1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamideand(4R)-4-hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide.

[0084] The present invention further comprises pharmaceuticalcompositions that include at least one compound according to theforegoing description as an active constituent. The composition may alsoinclude a second pharmacological agent such as a spasmolytic or apotassium channel blocker, these agents being known in the art toameliorate bladder dysfunction. Preferably, the composition includesonly one active constituent. The composition will include excipientsselected from binding agents, bulking agents, dispersants, solvents,stabilising agents and the like, such excipients being generally knownin the art.

[0085] The excipients used will depend on the intended nature of theformulation, which will, in turn, depend on the intended route ofadministration. Administration may be oral, transmucosal (such assublingual, buccal, intranasal, vaginal and rectal), transdermal or byinjection (such as subcutaneous, intramuscular and intravenous). Oraladministration is generally preferred. For oral administration, theformulation will be a tablet or capsule. Other formulations include drypowders, solutions, suspensions, suppositories and the like.

[0086] In a further aspect, the present invention is a method oftreating or controlling certain human physiological dysfunctions. Thismethod comprises the administration to the person in need of suchtreatment of an effective amount of a pharmaceutical composition, whichcomposition contains a compound according to the foregoing descriptionas an active constituent The compounds act to reduce urine output, andso the method of the invention can be applied to all conditions in whichelevated urine output is a contributory factor. The compounds alsoincrease the production of the blood coagulation proteins known asFactor VIII and von Willebrand factor, and so the treatment of bleedingdisorders can be undertaken.

[0087] In a preferred embodiment, the condition treated is centraldiabetes insipidus. This is a condition caused by an inability of thebody to produce and secrete physiologically active vasopressin, with theresult that water re-uptake is greatly reduced and large volumes ofurine are produced.

[0088] In another preferred embodiment, the condition treated isnocturnal enuresis. This is defined as bladder emptying while theindividual is sleeping. It is a condition that mainly affects childrenand a number of factors may be involved in its etiology.

[0089] In another preferred embodiment, the condition treated isnocturia. This is defined as production of sufficient urine during thenight to require the individual to wake and empty his (or her) bladder.Again, this condition may be the result of a number of factors.

[0090] In another preferred embodiment, the condition treated isincontinence. This condition is charactersed, in part, by reducedbladder capacity and control such that involuntary urination occursunless the bladder is emptied frequently. Incontinence has been dividedinto two conditions, stress incontinence and urge incontinence. A numberof etiological factors are thought to be involved. Treatment accordingto the invention is particularly useful for delaying the need forbladder emptying (“voiding postponement”) in order to allow theincontinent subject a dry period of a few hours (such as up to fourhours). Such voiding postponement may also be useful for thenon-incontinent population, for example for people obliged to remain inmeetings for extended periods.

[0091] In another preferred embodiment, the condition treated ishaemophilia A or von Willebrand's disease. This is a condition in whichFactor VII or von Willebrand factor production is reduced and theindividual suffers from prolonged bleeding.

[0092] In another preferred embodiment, the composition is administeredprior to surgery (including dental surgery) to increase thecoagulability of the blood and so reduce peri-operative blood loss.

[0093] The administration of the compositions of the present inventionwill generally be under the control of a physician. The physician willdetermine the amount of composition to be administered and the dosingschedule, taking into account the patient's physical condition and thetherapeutic goals. For an adult diabetes insipidus patient, a typicaldose might be between 50 mg and 1 g of the active compound per day,taken as a single tablet or as up to four tablets throughout the day.For routes of administration other than the oral route, the amount ofcompound will be reduced, since non-oral routes tend to be moreefficient in terms of delivering therapeutic agents into the systemiccirculation. For the treatment of von Willebrand's disease andhaemophilia A, the amount of compound may need to be higher than for thetreatment of diabetes insipidus.

[0094] The compounds of the present invention can be prepared usingmethods generally known in the art. The compounds of general formulae 1and 2 can be considered to be composed of three linked fragments, G¹, G²and the-central aromatic moiety (which will be referred to here as the“core”). Reagents corresponding to the three fragments will generally beprepared separately and then combined at a late stage in the synthesis.

[0095] Some instances of the various groups and substituents might beincompatible with this assembly and so will require the use ofprotecting groups. The use of protecting groups is well known in the art(see for example “Protective Groups in Organic Synthesis”, T. W. Greene,Wiley-lnterscience, 1981). Particular groups that may require protectionare amines (protected as amides or carbamates), alcohols (protected asesters or ethers) and carboxylic acids (protected as esters). For thepurposes of this discussion, it will be assumed that such protectinggroups as are necessary are in place.

[0096] The three fragments can be combined according to two strategiesto give the compounds of formulae 1 and 2. In the first, the fragmentscorresponding to G¹ and the core are linked to give a fragmentcorresponding to core-G¹, which is then combined with fragment G². Inthe second, the fragments the fragments corresponding to the core and G²are linked to give a fragment corresponding to G²-core, which is thencombined with fragment G¹. The ch mistry involved in the condensation offragment G¹ with the cor fragment, and that involved in the condensationof the core fragment with fragment G², will be the same whicheverstrategy is followed.

[0097] Formaton of Fragment Core-G¹

[0098] The synthesis of this fragment requires the formation of an amidebond between the two moieties. Reactions of this type are well known inthe art. Most conveniently, an acid chloride corresponding to the corefragment may be allowed to react with the free secondary amino group ofthe G¹ azepine ring. Such a reaction generally is performed in anaprotic solvent such as dichloromethane or dimethylformamide at orslightly below room temperature. A tertiary amine base such astriethylamine or dimethylaminopyridine is usually added. Alternatively,the carboxylic acid corresponding to the core fragment may be condensedwith the secondary amino group using one of the many reagents that havebeen developed for the formation of amide bonds in the field of peptidechemistry. Examples of such reagents include DCC(dicyclohexylcarbodiimide), BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate), PyBOP®((benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate),PyBroP® (bromotripyrrolidino-phosphonium hexafluorophosphate) and HBTU(O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate). Other reagents are also known. The details of thesynthetic method will depend on the particular reagent selected, butwill generaly involve the use of an aprotic solvent and a tertiary aminebase, as described above. Either the reagent is added to a mixture ofthe carboxylic acid and the azepine, or the carboxylic acid and thereagent are premixed to form a reactive intermediate (which is notisolated) to which is added the azepine.

[0099] Formation of Fragment G²-core

[0100] Depending on the nature of G², the G²-core bond can be part of anamide or thioamide, a sulphonamide, a urea or thiourea, a sulphonylureaor sulphonylthiourea, or a cyanoamidine, cyanoguanidine orsulphonylcyanoguanidine. The chemistry involved in the preparation ofthe G2-core bond will be different for each of these.

[0101] (i.a) Amides {G²=10, D=Covalent Bond, V=O}

[0102] These compounds can be formed by the reaction of a carboxylicacid or acid chloride corresponding to fragment G² with the primaryamino group of the core fragment. Conditions for the reaction willgenerally be similar to those described for the formation of the core-G¹bond, except that the primary amine is more reactive than the azepinenitrogen and so lower temperatures and shorter reaction times may beused.

[0103] (i.b) Thioamides {G²=10, D=covalent bond, V=S}

[0104] These compounds can be formed by the reaction of a suitablethiocarbonyl compound such as a dithioester (RCS₂R′) with the primaryamine in a manner analogous to that described for the correspondingamides above. Alternatively, they may be prepared from the correspondingamides (V=O) by reaction with Lawesson's reagent.

[0105] (ii) Sulphonamides {G²=9, d=1, e=Zero}

[0106] These compounds are generally prepared by the reaction of thesulphonyl chloride corresponding to the G² fragment with the primaryamine of the core fragment. The reaction is generally performed underconditions similar to those described above for the reaction of acarboxylic acid chloride with the primary amine that gives the amides.

[0107] (iii.a) Ureas {G²=9, d=Zero, e=1, V=O; G²=10, D=NH, V=O; G²=11,V=O}

[0108] These compounds can be prepared by the reaction of an amine withan isocyanate or an equivalent thereof. Due to the symmetry of the ureafunctional group, there is the possibility to choose which componentacts as the amine and which as the isocyanate. Most simply, when G² is agroup according to 9 or 10, the corresponding isocyanate is readilyaccessible. It can conveniently be reacted with the primary amine of thecore fragment in an aprotic solvent without the need for additionalreagents. When G² is a group according to 11, the isocyanate is notavailable, and the carbamoyl chloride can be used in its place. Thecarbamoyl chloride is generally prepared immediately prior to use bytreating the corresponding secondary amine with phosgene or anequivalent reagent such as diphogene or triphogene. Alternatively, theuse of carbonyl diimidazole leads to the formation of a carbamoylimidazole derivative that can be used in place of the carbamoylchloride. The reaction of the carbamoyl chloride with the primary aminegenerally requires the addition of a tertiary amine base to neutralisethe hydrogen chloride formed.

[0109] In some cases, it may be preferable to treat the primary aminecorresponding to the core fragment with phosgene (or carbonyldiimidazole) to form an isocyanate that can subsequently be reacted withthe primary or secondary amine corresponding to the G² fragment.

[0110] (iii.b) Thioureas {G²=9, d=Zero, e=1, V=S; G²=10, D=NH, V=S;G²=11, V=S}

[0111] These compounds can be prepared by methods analogous to thosedescribed above for the ureas, simply by using the correspondingisothiocyanate and thiophosgene compounds.

[0112] (iv.a) Sulphonylureas {G²=9, d=1, e=1, V=O}

[0113] These compounds can be prepared by the reaction of the primaryamine corresponding to the core fragment with an appropriate sulphonylisocyanate. The reaction conditions are similar to those described abovefor the reaction of an amine with an isocyanate to prepare the ureas.

[0114] (iv.b) Sulphonylthioureas {G²=9, d=1, e=1, V=S}

[0115] These compounds can be prepared analogously to the sulphonylureasby the reaction of the primary amine corresponding to the core fragmentwith an appropriate sulphonyl isothiocyanate.

[0116] (v.a) Cyanoamidines {G²=10, D=Covalent Bond, V=N—CN}

[0117] These compounds can be prepared by the reaction of the primaryamine of the core fragment with an N-cyanothioamide or anN-cyanothioimidate corresponding to the G² fragment.

[0118] (v.b) Cyanoguanidines {G²=9, d=Zero, e=1, V=N—CN; G²=10, D=NH,V=N—CN; G²=11, V=N—CN}

[0119] These compounds can be prepared by the reaction of the primaryamine of the core fragment with a cyanothiourea corresponding to the G²fragment in the presence of a carbodiimide.

[0120] (v.c) Sulphonylcyanoguanidines {G²=9, d=1, e=1, V=N—CN}

[0121] These compounds can be prepared in an analogous manner by thereaction of the pnmary amine of the core fragment with anN-sulphonyl-N′-cyanothiourea corresponding to the G² fragment in thepresence of a carbodiimide.

[0122] The reagents corresponding to the fragments are commerciallyavailable, or they can be prepared by methods described in theliterature. Particularly relevant leading references include thefollowing.

[0123] Synthesis of fused azepine derivatives for G¹:

[0124] Aranapakam et al., Bioorg. Med. Chem. Lett. 1993, 1733; Artico etal., Farmaco. Ed. Sci. 24, 1969, 276; Artico et al., Farmaco. Ed. Sci.32, 1977, 339; Chakrabarti et al., J. Med. Chem. 23, 1980, 878;Chakrabarti et al., J. Med. Chem. 23, 1980, 884; Chakrabarti et al., J.Med. Chem. 32, 1989, 2573; Chimirri et al., Heterocycles 36, 1993, 601;Grunewald et al., J. Med. Chem. 39, 1996, 3539; Klunder et al., J. Med.Chem. 35, 1992, 1887; Liegbois et al., J. Med. Chem. 37, 1994, 519;Olagbemiro et al., J. Het. Chem. 19, 1982, 1501; Wright et al., J. Med.Chem. 23, 1980, 462; Yamamoto et al., Tet. Lett. 24, 1983, 4711; andInternational patent application, publication number WO99/06403.

[0125] Synthesis of amidine transfer reagents for G², V=N—CN

[0126] Mestres et al., Synthesis, 1980, 755; Petersen et al., J. Med.Chem. 21, 1978, 773; and Cord, J. Chem. Soc., 1948, 1620.

[0127] Synthesis of proline derivatives for G²=group according to 11

[0128] Dugave et al., Tet. Lett. 39, 1998, 1169; Petrillo et al., J.Med. Chem. 31, 1988, 1148; and Smith et al., J. Med. Chem. 31, 1988,875.

[0129] The foregoing general description is further illustrated belowwith a number of non-limiting examples.

EXAMPLES

[0130] Abbreviations

[0131] The following abbreviations have been used. AIBNAzo-bis-(isobutyronitrile) BOC tert-Butyloxycarbonyl (BOC)₂ODi-tert-butyl dicarbonate DMF Dimethylformamide EtOAc Ethyl acetate IPAIsopropanol M.S. Mass spectrometry NBS N-Bromosuccinimide pet. etherpetroleum ether, fraction boiling at 60-80° C. THF Tetrahydrofuran WSCDIWater-soluble carbodiimide

[0132] Preparation of Intermediates

[0133] Reagents corresponding to fragments G¹ and G² were commerciallyavailable or prepared according to the published procedures except wheredetailed in the specific Examples. Reagents corresponding to the corefragment were prepared as detailed below.

Example A

[0134] 4-(tert-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid

[0135] A1. Methyl 4-bromomethyl-3-chlorobenzoate

[0136] To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol)and AIBN (0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18h. The mixture was allowed to cool to room temperature and thenconcentrated in vacuo. The residue was purified by flash chromatographyon silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%).

[0137] A2. 4-(tert-Butyloxycarbonylaminomethyl)-3-chlorobenzoic acid

[0138] To a saturated solution of ammonia in ethanol (170 ml) was addedmethyl 4-bromomethyl-3-chlorobenzoate from Example A1 (5.5 g, 20.9mmol). The mixture was stirred at room temperature for 1 hr and thenconcentrated in vacuo. The residue was triturated with diethyl ether andthe resultant white crystals were fiflered off and washed with morediethyl ether. To a solution of this solid in water (100 ml) were addedsolutions of (BOC)₂O (5.0 g, 23.0 mmol) in dioxan (100 ml) and sodiumhydroxide (1.86 g, 46.0 mmol) in water (100 ml). The mixture was stirredat room temperature for 18 h and then concentrated in vacuo. The aqueousresidue was acidified with citric acid and extracted withchloroform/IPA. The organic layer was washed with water, dried overMgSO₄, and concentrated in vacuo to give a white solid; yield 2.8 g(67%).

Example B

[0139] 4-(tert-Butyloxycarbonylaminomethyl)-3-nitrobenzoic acid

[0140] 4-Bromomethyl-3-nitrobenzoic acid (4.75 g, 18.2 mmol) was reactedfollowing the method of Example A2 to give a yellow solid; yield 2.6 g(49%).

Example C

[0141] 4Cyano-3methylbenzoic acid

[0142] To a solution of 4bromo-2-methylbenzonitrile (2.0 g, 10.2 mmol)in THF (100 ml) at −78° C. under a nitrogen atmosphere was addeddropwise a 2.5M solution of n-butyl lithium (4.48 ml, 11.2 mmol). Themixture was stirred at −78° C. for 1 h and then poured onto solid carbondioxide (5 g) in THF (50 ml). The mixture was allowed to warm to roomtemperature. Water was added (200 ml) and the mixture was extracted withdiethyl ether (3 times). The aqueous layer was acidified by addition ofconcentrated HCl and extracted with chloroform (3 times). The combinedchloroform extracts were washed with water, dried over MgSO₄, andconcentrated in vacuo to give a white solid; yield 1.2 g (73%).

Example D

[0143] 4-Cvano-2-methylbenzoic acid

[0144] 4Bromo-3methylbenzonitrile (2.0 g, 10.2 mmol) was reactedfollowing the method of Example C to give a yellow solid which wastriturated with hexane and filtered off; yield 0.96 g (59%).

Example E

[0145] 4-(tert-Butyloxycarbonylaminomethyl)-2-fluorobenzoic acid

[0146] E1.2-Fluoro-4-methylbenzoic acid

[0147] 4-Bromo-3-fluorotoluene (8.33 g, 44.07 mmol) was reactedfollowing the method of Example C to give a white solid; 4.89 g (72%).

[0148] E2. Methyl 2-fluoro-4-methylbenzoate

[0149] To a solution of 2-fluoro-4-methylbenzoic acid from Example E1(6.04 g, 39.18 mmol) in toluene (80 ml) was added thionyl chloride (65ml, 89.11 mmol). The mixture was heated at reflux for 2.5 h, cooled andconcentrated in vacuo. The residue was dissolved in dichloromethane (50ml) and methanol (50 ml) was added. The mbture was stirred at roomtemperature for 2.5 h and then concentrated in vacuo. The residue wasdissolved in dichloromethane (100 ml), washed with saturated sodiumbicarbonate solution and brine, dried over MgSO₄, and concentrated invacuo to give a tan solid; yield 5.07 g (77%).

[0150] E3. Methyl 4-bromomethyl-2-fluorobenzoate

[0151] Methyl 2-fluoro-4-methylbenzoate from Example E2 (5.07 g, 30.16mmol) was reacted following the method of Example of A1. The product waspurified by flash chromatography on silica (eluant EtOAc:pet. ether20:80); yield 5.9 g (80%).

[0152] E4.4(tert-Butyloxycarbonylaminomethyl)-2-fluorobenzoic acid

[0153] Methyl 4-bromomethyl-2-fluorobenzoate from Example E3 (5.9 g,24.13 mmol) was reacted following the method of Example A2. The productwas recrystallised from dioxan/pet. ether to give white crystals; yield2.46 g (38%).

Example F

[0154] 6-(tert-Butyloxycarbonylaminomethyl)-2-chloronicotinic acid

[0155] F1. Methyl 2-chloro-6-methylnicotinate

[0156] To a suspension of 2-chloro-6-methylnicotinic acid (5.3 g, 30.8mmol) in dichloromethane (100 ml) at 0° C. were added DMF (1 ml) andoxalyl chloride (3.2 ml, 36.9 mmol). The mixture was allowed to warmn toroom temperature and stirred for 5 h. The solvents were removed in vacuoand the residue was dissolved in dichloromethane (50 ml) and methanol(50 ml). The mixture was stirred at room temperature for 18 h and thenconcentrated in vacuo. The residue was dissolved in chloroform, washedwith saturated sodium bicarbonate solution and brine, dried over MgSO₄,and concentrated in vacuo to give a brown oil; yield 5.70 g (100%).

[0157] F2. Methyl 6-bromomethyl-2-chloronicotinate

[0158] Methyl 2-chloro-6-methyinicofinate from Example F1 (5.70 g, 30.8mmol) was reacted following the method of Example of A1. The product waspurified by flash chromatography on silica (eluant EtOAC:pet. ether20:80); yield 4.8 g (58%).

[0159] F3. Methyl6-(tert-butyloxycarbonylaminomethyl)-2-chloronicotinate

[0160] Methyl 6-bromomethyl-2-chloronicotinate from Example F2 (4.8 g,18.0 mmol) was reacted following the method of Example of A2 to give anoff white solid; yield 1.45 g (28%).

Example G

[0161] 6-(tert-Butyloxycarbonylaminomethyl)nicotinic acid

[0162] G1. Methyl 6-(bromomethyl)nicotinate

[0163] Methyl 6-methyinicotinate (5.0 g, 33.0 mmol) was reactedfollowing the method of Example A1. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 20:80); yield 3.7 g(49%).

[0164] G2. Methyl 6(azidomethyl)nicotinate

[0165] To a solution of methyl 6(bromomethyl)nicotinate from Example G1(2.0 g, 8.60 mmol) in DMF (15 ml) was added sodium azide (0.84 g, 12.9mmol). The mixture was stirred at room temperature for 18 h. EtOAc (100ml) was added and the mixture was washed with water (3 times), driedover MgSO₄, and concentrated in vacuo. The residue was purified by flashchromatography on silica (eluant EtOAc:pet ether 20:80) to give a yellowgum; yield 1.55 g (93%).

[0166] G3. Methyl 6-(tert-butyloxycarbonylaminomethyl)nicotinate

[0167] To a degassed solution of methyl 6-(azidomethyl)nicotinate fromExample G2 (1.6 g, 8.30 mmol) in methanol (50 ml) was added 10%palladium-on-carbon (0.15 g). Hydrogen gas was bubbled through themixture for 2 h at room temperature. The catalyst was removed byfiltration through a pad of celite and the filtrate was evaporated invacuo. The residue was dissolved in dichloromethane and cooled to 0° C.To this solution were added triethylamine (1.67 g, 16.0 mmol) and(BOC)₂O (2.17 g, 9.96 mmol). The mixture was allowed to warm to roomtemperature and stirred for 18 h, then concentrated in vacuo. Theresidue was dissolved in EtOAc and washed with water, dried over MgSO₄,and concentrated in vacuo. The residue was purified by flashchromatography on silica (eluant EtOAc:pet. ether 50:50) to give ayellow solid; yield 1.57 g (71%).

[0168] G4. 6-(tert-Butyloxycarbonylaminomethyl)nicotinic acid

[0169] To a solution of methyl6-(tert-butyloxycarbonylaminomethyl)nicotinate from Example G3 (1.56 g,5.84 mmol) in THF (20 ml) and water (5 ml) was added lithium hydroxidemonohydrate (0.37 g, 8.76 mmol). The mixture was stirred at roomtemperature for 18 h and then concentrated in vacuo. The aqueous residuewas acidified by addition of 1M citric acid solution and extracted withchloroform/IPA (3 times). The combined organic extracts were washed withbrine, dried over MgSO₄, and evaporated in vacuo to give a white solid;yield 1.38 g (94%).

Example H

[0170]4/5-Bromo-6-(tert-butyloxycarbonylaminomethyl)-1-methyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylicacid

[0171] H1. Methyl 1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate

[0172] To a solution of 3-hydroxy-6-methyinicotinic acid (10 g, 65.0mmol) in DMF (100 ml) at 0° C. was added sodium hydride (4.83 g, 60%dispersion, 140 mmol). The mixture was stirred at 0° C. for 1.5 h, thenmethyl iodide (12.4 ml, 195 mmol) was added and the mixture was allowedto warm to room temperature, stirring for a further 18 h. The mixturewas partitioned between water and EtOAc and the aqueous layer acidifiedto pH 5. The layers were separated and the organic layer was washed withbrine, dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography on silica (eluantdichloromethane/methanol 95:5) to give a white solid. This wasrecrystallised from methanol and the filtrate was evaporated in vacuo togive the desired product; yield 6.1 g (52%).

[0173] H2. Methyl4/5-bromo-6-bromomethyl-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate

[0174] Methyl 1,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate ofExample H1 (6.0 g, 33.0 mmol) was reacted following the method ofExample of A1. The product was purified by flash chromatography onsilica (eluant dichloromethane/methanol 95:5); yield 5.2 g (46%).

[0175] H3.4/5-Bromo-6-(tert-butyloxycarbonylaminomethyl)-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylicacid

[0176] Methyl4/5-bromo-6-bromomethyl-1-methyl-2-oxo-1,2dihydropyridine-3-carboxylateof Example H2 (5.2 g, 14.8 mmol) was reacted following the method ofExample A2 to give a brown gum; yield 1.3 g (24%).

Example I

[0177] 4-Cyano-3,5-dimethylbenzoic acid

[0178] I1. 4-Bromo-2,6-dimethylbenzonitrile

[0179] 4-Bromo-2,6dimethylaniline (4.49 g, 22.4 mmol) was taken up inwater (25 ml) and concentrated hydrochloric acid (8.0 ml) was added. Themixture was sonicated to form a fine suspension and then cooled to 0° C.A solution of sodium nitrite (1.67 g, 24.2 mmol) in water (5 ml) wasthen added dropwise so as to maintain the temperature of the reactionbetween 0-5° C. The mixture was stirred at 0-5° C. for ½ h and thenneutralised by addition of solid sodium carbonate. The resultingsolution was then added portionwise to a solution of copper cyanide(2.42 g, 27.0 mmol) and potassium cyanide (3.65 g, 56.1 mmol) in water(25 ml) at 70° C. The mixture was stirred at 70° C. for ½ h, allowed tocool and then extracted with toluene (2 times). The combined extractswere washed with water and brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by flash chromatography on silica(eluant EtOAc:pet. ether 5:95) to give an orange solid; yield 3.2 g(68%).

[0180] I2. 4-Cyano-3,5-dimethylbenzoic acid

[0181] 4-Bromo-2,6-dimethylbenzonitrile from Example I1 (3.20 g, 15.2mmol) was reacted following the method of Example C to give a tan solid;yield 1.5 g (56%).

[0182] Reagents corresponding to fragments A, B and C were combined togive the specific Examples as detailed below.

Example 1

[0183]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0184] 1A. 1-(4-Cyanobenzoyl)-2.3,4,5-tetrahydro-1H-1-benzazepine

[0185] To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (1.05 g,7.14 mmol) in dichloromethans (40 ml) were added 4-cyanobenzoic acid(1.26 g, 8.57 mmol), triethylamine (1.00 g, 7.14 mmol),4-(dimethylamino)pyridine (0.87 g, 7.14 mmol) and WSCDI (2.86 g, 14.28mmol). The mixture was stirred at reflux for 18 h, cooled and evaporatedin vacuo. The residue was partitioned between EtOAc and 1M KHSO₄. Theorganic layer was washed with saturated sodium bicarbonate solution andbrine, dried over MgSO₄, and concentrated in vacuo to give a whitesolid; yield 1.50 g (76%).

[0186] 1B.1-(4-(Aminomethyl)benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0187] To a degassed solution of the cyanobenzoyl benzaz pin fromExample 1A (1.50 g, 5.43 mmol) in methanol (50 ml) were addedconcentrated hydrochloric acid (1.4 ml, 16.2 mmol) and 10%palladium-on-carbon (1.15 g). Hydrogen gas was bubbled through themixture for 5 h at room temperature. The catalyst was removed byfiltration through a pad of celite and the filtrate was evaporated invacuo. The residue was partitioned between EtOAc and water. The aqueouslayer was basified by addition of saturated sodium bicarbonate solutionand extracted with dichloromethane (2 times). The combined organicextracts were washed with brine, dried over MgSO₄, and concentrated invacuo to give a white solid; yield 1.12 g (74%).

[0188] 1C.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0189] To a solution of the amine from Example 1B (0.50 g, 1.79 mmol) indichloromethane (20 ml) were added triethylamine (0.27 ml, 1.97 mmol)and 2,6-difluorophenylisocyanate (0.31 g, 1.97 mmol). The mixture wasstirred at room temperature for 2 h and then evaporated in vacuo. Theresidue was purffied by flash chromatography on silica (eluantEtOAc:pet. ether 50:50) to give a white solid; yield 0.62 g (80%).

[0190] M.S.: calc m/e=435.18; found [M+H]⁺=436.

Example 2

[0191]1-(4-[3-(2,6-Difluorophenyl)cyanoguanidinomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0192] To a solution of the amine from Example 1B (0.12 g, 0.379 mmol)in DMF (20 ml) were added 1-(2,6-difluoro-phenyl)-3-cyano-thiourea (0.16g, 0.758 mmol, prepared according to Atwal et. al., Tetrahedron Lett.,30, p7313, 1989.), diisopropylethylamine (0.16 ml, 0.947 mmol) and WSCDI(0.0879, 0.455 mmol). The mixture was stirred at room temperature for 72h and then evaporated in vacuo. The residue was partitioned betweendichloromethane and 1M KHSO₄. The organic layer was washed withsaturated sodium bicarbonate solution and brine, dried over MgSO₄ andconcentrated in vacuao. The residue was purified by flash chromatographyon silica (eluant EtOAc:pet. ether 50:50-70:30) to give a white solid;yield 0.084 g (48%).

[0193] M.S.: calc m/e=459.19; found [M+H]⁺=460.0

Example 3

[0194]1-(6-[3-(2,6-Difluorophenyl)ureidomethyl]nicotinoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0195] 3A.1-[6-(tert-Butyloxycarbonylaminomethyl)nicotinoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine

[0196] The carboxylic acid from Example G4 (1.38 g, 5.45 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.50 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 30:7070:30);yield 1.14 g (55%).

[0197] 3B.1-[6-(Aminomethyl)nicotinoyl]-2,3,4,5-tetrahydro-1H-1-benzazepinehydrochloride

[0198] The BOC amine from Example 3A (1.14 g, 2.98 mmol) was dissolvedin 4N HCl/dioxan, stirred at room temperature for 1 h and thenevaporated in vacuo, azeotroping with toluene, to give an off whitesolid; yield 1.0 g (quantitative).

[0199] 3C.1-(6-[3-(2,6-Difluorophenyl)ureidomethyl]nicotinoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0200] The amine hydrochloride from Example 3B (0.070 g, 0.220 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.038 g, 0.242 mmol)according to the procedure in Example 1C. Th product was purified bytrituration with diethyl ether to give a white solid; yield 0.060 g(63%).

[0201] M.S.: calc m/e=436.47; found [M+H]⁺=437.2.

Example 4

[0202]1-(3-Chloro-4-[3-(3-methoxyphenyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0203] 4A.1-(4-[tert-Butyloxycarbonylaminomethyl]-3-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0204] The carboxylic acid from Example A2 (1.0 g, 3.50 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.47 g, 3.20 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 30:70-40:60);yield 0.88 g (66%).

[0205] 4B.1-(4-[Aminomethyl]-3-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepinehydrochloride

[0206] The BOC amine from Example 4A (0.88 g, 2.10 mmol) was dissolvedin 4N HCl/dioxan and stirred at room temperature for 1 h, thenevaporated in vacuo, azeotroping with toluene, to give a white solid;yield 0.70 g (95%).

[0207] 4C.1-(3-Chloro-4-[3-(3-methoxyphenyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0208] The amine hydrochloride from Example 4B (0.0509, 0.140 mmol) wasreacted with 3-methoxyphenylisocyanate (0.021 g, 0.140 mmol) accordingto the procedure in Example 1C. The product was purified by triturationwith diethyl ether to give a white solid; yield 0.060 g (93%).

[0209] M.S.: calc m/e=463.17; found [M+H]⁺=464.2.

Example 5

[0210]1-(3-Chloro-4-[3-(2-chloropheny)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0211] The amine hydrochloride from Example 4B (0.050 g, 0.140 mmol) wasreacted with 2-chlorophenylisocyanate (0.022 g, 0.140 mmol) according tothe procedure in Example 1C. The product was purified by triturationwith diethyl ether to give a white solid; yield 0.063 g (98%).

[0212] M.S.: calc m/e=467.12; found [M+H]⁺; ³⁵Cl=468.1.

Example 6

[0213]1-(3-Chloro-4-[3-(2,6-difluorophenyl)thioureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0214] The amine hydrochloride from Example 4B (0.075 g, 0.214 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.054 g, 0.320 mmol)according to the procedure in Example 1C. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 30:7045:55);yield 0.068 g (66%).

[0215] M.S.: calc m/e=485.11; found [M+H]⁺; ³⁵Cl=486.2, [M+H]⁺;³⁷Cl=488.1

Example 7

[0216]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0217] 7A.1-(4-Cyano-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0218] The carboxylic acid from Example D (0.96 g, 5.95 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.44 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield0.59 g (38%).

[0219] 7B.1-(4-[Aminomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepinehydrochloride

[0220] The cyanobenzoyl benzazepine from Example 7A (0.59 g, 2.03 mmol)was hydrogenated according to the procedure in Example 1B. The productwas isolated as the HCl salt; yield 0.55 g (82%).

[0221] 7C.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-2-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0222] The amine hydrochloride from Example 7B (0.050 g, 0.151 mmol) wasreacted with 2,6difluorophenylisocyanate (0.028 g, 0.181 mmol) accordingto the procedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 50:50); yield 0.041 g(62%).

[0223] M.S.: calc m/e=449.19; found [M+H]⁺=450.1.

Example 8

[0224]1-(3-Methyl-4-[3-(phenylsulfonyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0225] 8A.1-(4-Cyano-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0226] The carboxylic acid from Example C (0.96 g, 5.95 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g, 5.44 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield1.10 g (70%).

[0227] 8B.1-(4-[Aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepinehydrochloride

[0228] The cyanobenzoyl benzazepine from Example 8A (1.10 g, 3.79 mmol)was hydrogenated according to the procedure in Example 1B. The productwas isolated as the HCl salt; yield 1.23 g (98%).

[0229] 8C.1-(3-Methyl-4-[3-(Phenylsufonyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0230] The amine hydrochloride from Example 8B (0.050 g, 0.151 mmol) wasreacted with phenylsulphonylisocyanate (0.028 g, 0.151 mmol) accordingto the procedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 80:20); yield 0.026 g(22%).

[0231] M.S.: calc m/e=477.17; found [M+H]⁺=478.2.

Example 9

[0232]1-(3-Methyl-4-[3-(2-oxo-1,2-dihydropyrid-3-yl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0233] To a suspension of 2-hydroxynicotinic acid (95 mg, 0.68 mmol) indioxan (5 ml) were added triethylamine (0.11 ml, 0.771 mmol) anddiphenylphosphoryl azide (0.16 ml, 0.725 mmol). The mixture was stirredat reflux for 3 h. The amine hydrochloride from Example 8B (0.15 g,0.453 mmol) and triethylamine (0.095 ml, 0.680 mmol) were added and themixture was stirred at reflux for a further 18 h, cooled and evaporatedin vacuo. The residue was partitioned between dichloromethane and 1 MKHSO₄. The organic layer was washed with saturated sodium bicarbonatesolution and brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica (eluantmethanol:dichloromethane 2:98-5:95) to give a white solid; yield 0.084 g(43%). M.S.: calc m/e=430.20; found [M+H]⁺=431.1.

Example 10

[0234]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0235] The amine hydrochloride from Example 8B (0.050 g, 0.151 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.028 g, 0.181 mmol)according to the procedure in Example 1C. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 50:50); yield0.044 g (65%).

[0236] M.S.: calc m/e=449.19; found [M+H]⁺=450.1.

Example 11

[0237]1-(3-Nitro-4-[2-nitrobenyzlsulfonylaminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0238] 11A.1-(4-[tert-Butyloxycarbonylaminomethyl]-3-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0239] The carboxylic acid from Example B (0.911 g, 3.08 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.453 g, 3.08 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 50:50); yield0.58 g (43%).

[0240] 11B.1-(4-[Aminomethyl]-3-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepinehydrochloride

[0241] The BOC-aminomethylbenzoyl benzazepine from Example 11A (0.33 g,0.764 mmol) was reacted according to the procedure in Example 4B. Theproduct was isolated as the HCl salt; yield 0.27 g (98%).

[0242] 11C.1-(3-Nitro-4-[2-nitrobenyzlsulfonylaminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0243] The amine hydrochloride from Example 11B (0.068 g, 0.188 mmol)was reacted with 2-nitrobenzylsulphonyl chloride (0.033 g, 0.226 mmol)according to the procedure in Example 1C. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 25:7550:50);yield 0.010 g (10%).

[0244] M.S.: calc m/e=524.14; found [M+H]⁺=525.2.

Example 12

[0245] 1-(3-Amino-4-[3-(2,6difluorophenyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0246] 12A.1-(3Amino-4-[tert-butyloxecarbonylaminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0247] To a degassed solution of the nitrobenzoyl benzazepine fromExample 11A (0.30 g, 0.700 mmol) in methanol (50 ml) was added 10%palladium-on-carbon (0.10 g). Hydrogen gas was bubbled through themixture for 1.5 h at room temperature. The catalyst was removed byfiltration through a pad of celite and the filtrate was evaporated invacuo; yield 0.254 g (92%).

[0248] 12B.1-(3-Amino-4-[aminomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benrzazepinedihydrochloride

[0249] The BOC-aminomethylbenzoyl benzazepine from Example 12A (0.14 g,0.354 mmol) was reacted according to the procedure in Example 4B. Theproduct was isolated as the diHCl salt; yield 0.098 g (75%).

[0250] 12C.1-(3-Amino-4-[3-(2,6-difluorophenyl)ureidomethyl]benzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0251] The amine hydrochloride from. Example 12B (0.132 g, 0.35 mmol)was reacted with 2,6-difluorophenylisocyanate (0.055 g, 0.35 mmol)according to the procedure in Example 1C. The product was purified byflash chromatography on silica (eluant EtOAc:pet. eth r 70:30) and thenby preparative HPLC (gradient water:acetonitrile 80:20-20:80; 0.1% TFA).The HPLC fractions were freeze-dried to give a white solid; yield 0.027g (17%).

[0252] M.S.: calc m/e=450.19; found [M+H]⁺=451,2.

Example 13

[0253]1-(4-[3-(2,6-Difluorophenyl)ureldomethyl]-3-dimethylaminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0254] 13A.1-(4-[tert-Butyloxycarbonylaminomethyl]-3-dimethylaminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0255] To an ice cold solution of the amine from Example 12A (0.16 g,0.40 mmol) in 1% acetic acid/methanol (25 ml) was added formaldehyde(37% solution in water, 0.050 ml, 0.60 mmol). The mixture was stirred at0° C. for 10 min and then sodium borohydride (0.050 g, 0.80 mmol) wasadded. The mixture was allowed to warm to room temperature with stirringover 1 h. and then evaporated in vacuo. The residue was partitionedbetween EtOAc and saturated sodium bicarbonate solution. The organiclayer was washed with brine, dried over MgSO₄, and concentrated invacuo. The residue was purified by flash chromatography on silica(eluant EtOAc:pet. ether 30:70-70:30) to give a white solid; yield 0.091g (56%).

[0256] 13B.1-(4-[Aminomethyl]-3-dimethylaminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0257] The BOC-aminomethylbenzoyl benzazepine from Example 13A (0.089 g,0.225 mmol) was reacted according to the procedure in Example 4B. Theproduct was isolated as the HCl salt; yield 0.075 g (97%).

[0258] 13C.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-dimethylaminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0259] The amine hydrochloride from Example 13B (0.075 g, 0.20 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.032 g, 0.20 mmol) accordingto the procedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 90:10); yield 0.044 g(65%).

[0260] M.S.: calc m/e=478.22; found [M+H]⁺=479.2.

Example 14

[0261]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-2-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0262] 14A.1-(4-[tert-Butyloxycarbonylaminomethyl]-2-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0263] The carboxylic acid from Example E4 (0.60 g, 2.22 mmol) wasreacted with 2,3,4,5-t trahydro-1H-1-benzazepin (0.289, 1.89 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 40:60); yield0.58 g (77%).

[0264] 14B.1-(4-[Aminomethyl]-2-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0265] The BOC-aminomethylbenzoyl benzazepine from Example 14A (0.58 g,1.42 mmol) was reacted according to the procedure in Example 4B. Theproduct was isolated as the HCl salt; yield 0.29 g (60%).

[0266] 14C.1-(4-[3-(2,6-Difluorophenyl)ureidomethy]-2-fluorobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0267] The amine hydrochloride from Example 14B (0.040 g, 0.12 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.020 g, 0.13 mmol) accordingto the procedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 40:60-100:0); yield0.038 g (70%).

[0268] M.S.: calc m/e=453.17; found [M+H]⁺=454.1.

Example 15

[0269]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0270] 15A. 2,3,4,5-Tetrahydro-1H-1,5-benzodiazepine

[0271] To an ice cold solution of lithium aluminium hydride (4.68 g, 123mmol) in dry THF (100 ml), under a nitrogen atmosphere, was addeddropwise a solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one(5.0 g, 30.9 mmol) in dry THF (50 ml). The mixture was allowed to warmto room temperature and then heated at reflux for 2 h. The mixture wasthen cooled to 0° C. and a solution of aqueous ammonium hydroxide (10ml) in THF (60 ml) was added dropwise. The resultant suspension wasstirred for 1 h and then filtered through a pad of celite. The filtratewas evaporated in vacuo to give a tan solid; yield 4.36 g (95%).

[0272] 15B.1-(4-Cyano-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0273] The carboxylic acid from Example C (0.65 g, 4.03 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 15A(0.50 g, 3.36 mmol) according to the procedure in Example 1A. Theproduct was purified by flash chromatography on silica (eluantEtOAc:pet. ether 50:50); yield 0.36 g (37%).

[0274] 15C.1-(4-[Aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride

[0275] The cyanobenzoyl benzodiazepine from Example 15B (0.36 g, 1.24mmol) was hydrogenated according to the procedure in Example 1B. Theproduct was isolated as the HCl salt; yield 0.17 g (40%).

[0276] 15D.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0277] The amine hydrochloride from Example 15C (0.170 g, 0.46 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.071 g, 0.46 mmol) accordingto the procedure in Exampl 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 80:20); yield 0.089 g(43%).

[0278] M.S.: calc m/e=450.19; found [M+H]⁺=451.2.

Example 16

[0279]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5-(3-Pyridyl)methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0280] 16A. 1-(3-Pyridyl)methyl-2,3,4,5-tetrahydro-1H-1.5-benzodiazepine

[0281] To solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepine fromExample 15A (0.50 g, 3.38 mmol) in 1% acetic acid/methanol (25 ml), atroom temperature, was added pyridine-3-carboxaldehyde (0.35 ml, 03.72mmol). The mixture was stirred at reflux for 18 h and then allowed tocool to room temperature. Sodium borohydride (0.050 g, 0.80 mmol) wasadded. The mixture was stirred for 2 h and then evaporated in vacuo. Theresidue was partitioned between EtOAc and saturated sodium bicarbonatesolution. The organic layer was washed with brine, dried over MgSO₄, andconcentrated in vacua. The residue was purified by flash chromatographyon silica (eluant EtOAc) to give a white solid; yield 0.386 g (40%).

[0282] 16B.1-(4-Cyano-3-methylbenzoyl)-5-(3-pyridyl)methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0283] The carboxylic acid from Example C (0.31 g, 1.93 mmol) wasreacted with1-(3-pyridyl)methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine fromExample 16A (0.39 g, 1.61 mmol) according to the procedure in Example1A. The product was purified by flash chromatography on silica (eluantEtOAc); yield 0.28 g (45%).

[0284] 16C.1-(4-Aminomethyl-3-methylbenzoyl)-5-(3-pyridyl)methyl-2,3,4,5-tetrahydro-1H-1.5-benzodiazepine

[0285] To a solution of the nitrile from Example 16B (0.28 g, 0.72 mmol)in methanol (20 ml) were added cobaltous chloride (0.338 g, 1.42 mmol)and sodium borohydride (0.27 g, 7.20 mmol). The mixture was stirred atroom temperature for 1 h and then saturated aqueous ammonium chloridesolution (10 ml) was added. The mixture was concentrated in vacuo andthe aqueous residue was partitioned between diethyl ether and water. Theaqueous layer was basified by addition of saturated sodium bicarbonatesolution and extracted with chloroform (3 times). The combined organicextracts were washed with brine, dried over MgSO₄, and concentrated invacuo to give a white solid; yield 0.20 g (7.2%).

[0286] 16D.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5-(3-pyridyl)methyl-2,3,4-tetrahydro-1H-1,5-benzodiazepine

[0287] The amine from Example 16C (0.065 g, 0.168 mmol) was reacted with2,6-difluorophenylisocyanate (0.027 g, 0.17 mmol) according to theprocedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc); yield 0.068 g (75%).

[0288] M.S.: calc m/e=541.23; found [M+H]⁺=542.2.

Example 17

[0289]1-(4-[3-(2,6Difuorophenyl)ureidomethyl]-3-methylbenzoyl)-5-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0290] 17A. Methyl(2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)acetate

[0291] To a solution of 1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one(5.0 g, 30.8 mmol) in DMF (30 ml), at −10° C., was added sodium hydride(1.35 g, 60% dispersion, 33.9 mmol). The mixture was stirred at −10° C.for 15 min, then methyl bromoacetate (2.92 ml, 30.8 mmol) was added. Themixture was stirred at −10° C. for a further 1 h and then concentratedin vacuo. The residue was taken up in EtOAc and washed with brine (3times), dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography on silica (eluant EtOAc) to give awhite solid; yield 7.08 g (98%).

[0292] 17B. 2-(2,3,4,5-Tetrahydro-1H-1,5-benzodiazepin-1-yl)ethanol

[0293] Methyl(2-oxo-[1,3,4,5-tetrahydro-benzo[b]1,4]diazepin-1-yl)-acetate fromExample 17A (7.08 g, 30.2 mmol) was reduced with lithium aluminiumhydride according to the procedure in Example 15A; yield 4.33 g (75%).

[0294] 17C.1-(4-Cyano-3-methylbenzoyl)-5-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0295] To a solution of the carboxylic acid from Example 1C (1.38 g,8.58 mmol) in dichloromethane (50 ml) was added thionyl chloride (3.33ml, 43.0 mmol). The mixture was stirred at reflux for 2 h and thenevaporated in vacuo, azeotroping with toluene (2 times). The residue wasdissolved in dichloromethane (50 ml) and2-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl)ethanol from Example 17B(1.5 g, 7.80 mmol) was added. The mixture was stirred at roomtemperature for 18 h and then evaporated in vacuo. The residue waspartitioned between EtOAc and saturated sodium bicarbonate solution. Theorganic layer was washed with brine, dried over MgSO₄, and concentratedin vacuo. The residue was triturated with EtOAc and the resultant solidfiltered off; yield 1.25 g (48%).

[0296] 17D.1-(4-Aminomethyl-3-methylbenzoyl)-5-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1.5-benzodiazepine

[0297] The cyanobenzoyl benzodiazepine from Example 17C (1.25 g, 3.73mmol) was hydrogenated according to the procedure in Example 1B. Theproduct was isolated as the free base; yield 0.94 g (74%).

[0298] 17E.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0299] The amine from Example 17D (0.94 g, 2.76 mmol) was reacted with2,6-difluorophenylisocyanate (0.47 g, 3.04 mmol) according to theprocedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc); yield 0.068 g (75%).

[0300] M.S.: calc m/e=494.21; found [M+H]³⁰ =495.2.

Example 18

[0301]1-(3-Chloro-4-[3-(2,6-difluorophenyl)ureidomethyl]benzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0302] 18A. 1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0303] To a solution of 2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one(2.0 g, 12.3 mmol) in DMF (30 ml), at −10° C., was added sodium hydride(0.54 g, 60% dispersion, 13.6 mmol). The mixture was stirred at −10° C.for 15 min, then methyl iodide (0.77 ml, 12.3 mmol) was added. Themixture was stirred at −100° C. for a further 1 h and then concentratedin vacuo. The residue was taken up in EtOAc and washed with brine (3times), dried over MgSO₄, and concentrated in vacuo. The residue waspurified by flash chromatography on silica (eluant EtOAc) to give awhite solid; yield 1.70 g (78%).

[0304] 18B. 1-Methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0305] 1-Methyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine fromExample 18A (1.7 g, 9.65 mmol) was reduced with lithium aluminiumhydride according to the procedure in Example 15A; yield 1.34 g (86%).

[0306] 18C.1-(4-[tert-Butyloxycarbonylaminomethyl]-3-chlorobenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0307] The carboxylic acid from Example A2 (0.506 g, 1.77 mmol) wasreacted with 1-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine fromExample 18B (0.24 g, 1.48 mmol) according to the procedure in Example1A. The product was purfied by flash chromatography on silica (eluantEtOAc:pet. ether 50:50); yield 0.30 g (47%).

[0308] 18D.1-(4-Aminomethyl-3-chlorobenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0309] The BOC-aminomethylbenzoyl benzazodiazepine from Example 18C(0.30 g, 0.698 mmol) was reacted according to the procedure in Example4B. The product was isolated as the HCl salt; yield 0.25 g (98%).

[0310] 18E.1-(3-Chloro-[4-3-(2,6-difluorophenyl)ureidomethyl]benzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0311] The amine hydrochloride from Example 18D (0.060 g, 0.164 mmol)was reacted with 2,6-difluorophenylisocyanate (0.021 g, 0.164 mmol)according to the procedure in Example 1C. The product was purified bytrituration with diethyl ether to give a white solid; yield 0.058 g(87%).

[0312] M.S.: calc m/e=484.15; found [M+H]⁺; ³⁵Cl=485.1.

Example 19

[0313]1-(4-[3-(2,6-Difluorophenyl)uredomethyl]-2-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0314] 19A.1-(4-Cyano-2-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride

[0315] The carboxylic acid from Example D (0.50 g, 3.10 mmol) wasreacted with 1-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine fromExample 18B (0.46 g, 2.80 mmol) according to the procedure in Example1A. The product was purified by flash chromatography on silica (eluantEtOAc:pet. ether 30:70-70:30); yield 0.27 g (32%).

[0316] 19B.1-(4-Aminomethyl-2-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazecinehydrochloride

[0317] The cyanobenzoyl benzazepine from Example 19A (0.26 g, 0.88 mmol)was hydrogenated according to the procedure in Example 1B. The productwas isolated as the HCl salt; yield 0.30 g (99%).

[0318] 19C.1-(4-[(2,6-Difluorophenyl)ureidomethyl]-2-methylbenzoyl)-5-methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0319] The amine hydrochloride from Example 19B (0.060 g, 0.17 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.027 g, 0.17 mmol) accordingto the procedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 80:20); yield 0.070 g(93%).

[0320] M.S.: calc m/e=464.20; found [M+H]⁺=465.2.

Example 20

[0321]1-(4-[3-(2,6-Difluorophenyl)uredorethyl]-3,5-dimethylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0322] 20A.1-(4-Cyano-3,5-dimethylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0323] The carboxylic acid from Example I2 (0.49 g, 2.80 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.39 g, 2.63 mmol)according to the procedure in Example 17C. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 30:70); yield0.66 g (77%).

[0324] 20B.1-(4-Aminomethyl-3,5-dimethylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0325] The nitrile from Example 20A (0.65 g, 2.12 mmol) was reducedaccording to the procedure in Example 16C; yield 0.42 g (64%).

[0326] 20C.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3,5-dimethylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0327] The amine from Example 20B (0.070 g, 0.23 mmol) was reacted with2,6-difluorophenylisocyanate (0.043 g, 0.28 mmol) according to theprocedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 40:60); yield 0.033 g(31%).

[0328] M.S.: calc m/e=463.21; found [M+H]⁺=464.2.

Example 21

[0329]1-(2-Chloro-6-[3-(2,6-difluorophenyl)ureidomethyl]nicotinoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0330] 21A.1-(6-[tert-Butylaminomethyl]-2-chloronicotinoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0331] The carboxylic acid from Example F3 (0.50 g, 1.74 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.26 g, 1.74 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 55:45); yield0.038 g (5%).

[0332] 21B.1-(6-Aminomethyl-2-chloronicotinoyl)-2,3,4,5-tetrahydro-1H-1-benzazepinehydrochloride

[0333] The BOC-aminomethylnicotinoyl benzazepine from Example 21A (0.036g, 0.074 mmol) was reacted according to the procedure in Example 4B. Theproduct was isolated as the HCl salt; yield 0.026 g (98%).

[0334] 21C.1-(2-Chloro-6-[(2,6-difluorophenyl)ureidomethyl]nicotinoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0335] The amine hydrochloride from Example 21B (0.026 g, 0.073 mmol)was reacted with 2,6-difluorophenylisocyanate (0.014 g, 0.08 mmol)according to the procedure in Example 1C. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 90:10); yield0.031 g (90%).

[0336] M.S.: calc m/e=470.13; found [M+H]⁺; ³⁵Cl=471.1.

Example 22

[0337]1-(6-[3-(2,6-Difluorophenyl)ureidomethyl]-1-methyl-2-oxo-1,2-dihydropyridyl-3-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0338] 22A.1-(4/5-Bromo-6-[tert-butyloxycarbonylaminomethyl]-1-methyl-2-oxo-1,2-dihydropyridyl-3-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0339] The carboxylic acid from Example H3 (1.30 g, 3.60 mmol) wasreacted with 2,3,4,5-tetrahydro-1H-1-benzazepine (0.53 g, 3.60 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield0.70 g (40%).

[0340] 22B.1-(4/5-Bromo-6-[tert-butyloxycarbonylaminomethyl]-1-methyl-2-oxo-1,2-dihydropyridyl-3-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0341] The benzazepine from Example 22A (0.60 g, 1.23 mmol) washydrogenated according to the procedure in Example 12A; yield 0.50 g(99%).

[0342] 22C.1-(6-Aminomethyl-1-methyl-2-oxo-1,2-dihydropyridyl-3-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzazpin hydrochloride

[0343] The BOC-aminomethyl pyridone from Example 22B (0.50 g, 1.22 mmol)was reacted according to the procedure in Example 4B. The product wasisolated as the HCl salt; yield 0.43 g (99%).

[0344] 22D.1-(6-[3-(2,6-Difluorophenyl)ureidomethyl]-1-methyl-2-oxo-1,2-dihydropyridyl-3-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0345] The amine hydrochloride from Example 22C (0.050 g, 0.144 mmol)was reacted with 2,6-difluorophenylisocyanate (0.025 g, 0.144 mmol)according to the procedure in Example 1C. The product was purified byflash chromatography on silica (eluant EtOAc:methanol 90:10); yield0.064 g (95%).

[0346] M.S.: calc m/e=466.18; found [M+H]⁺=467.2.

Example 23

[0347]1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0348] 23A. 1-Ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0349] 2-Oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (1.95 g, 11.96mmol) was reacted with ethyl iodide (1.4 ml, 17.5 mmol) according to theprocedure in Example 18A. The product was purified by flashchromatography on silica (eluant EtOAc); yield 1.70 g (75%).

[0350] 23B. 1-Ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0351] 1-Ethyl-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine fromExample 23A (1.7 g, 8.94 mmol) was reduced with lithium aluminiumhydride according to the procedure in Example 15A; yield 1.55 g (98%).

[0352] 23C.1-(4-Cyano-3-methylbenzoyl)-5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0353] The carboxylic acid from Example C (0.53 g, 3.29 mmol) wasreacted with 1-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine fromExample 23B (0.514 g, 2.92 mmol) according to the procedure in Example1A. The product was purified by flash chromatography on silica (eluantEtOAc:pet. ether 60:40); yield 0.55 g (59%).

[0354] 23D.1-(4-Aminomethyl-3-methylbenzoyl)-5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepinehydrochloride

[0355] The nitrile from Example 23C (0.55 g, 1.73 mmol) was hydrogenatedaccording to the procedure in Example 1B. The product was isolated asthe HCl salt; yield 0.60 g (96%).

[0356] 23E.1-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine

[0357] The amine hydrochloride from Example 23D (0.071 g, 0.20 mmol) wasreacted with 2,6-difluorophenylisocyanate (0.038 g, 0.25 mmol) accordingto the procedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc:pet. ether 50:50-100:0); yield0.044 g (46%).

[0358] M.S.: calc m/e=478.22; found [M+H]⁺=479.2.

Example 24

[0359]5-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine

[0360] 24A.5-(4-Cyano-3-methylbenzoyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3b]azepine

[0361] The carboxylic acid from Example C (0.36 g, 2.26 mmol) wasreacted with 6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine (0.33 g, 2.23mmol) according to the procedure in Example 17C. The product waspurified by flash chromatography on silica (eluant EtOAc:pet. ether80:20); yield 0.47 g (73%).

[0362] 24B.5-(4-Aminomethyl-3-methylbenzoyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine

[0363] The cyanobenzoyl pyridoazepine from Example 24A (0.46 g, 1.58mmol) was hydrogenated according to the procedure in Example 1B. Theproduct was isolated as the free base; yield 0.28 g (60%).

[0364] 24C.5-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepine

[0365] The amine from Example 24B (0.071 g, 0.20 mmol) was reacted with2,6-difluorophenylisocyanate (0.035 g, 0.23 mmol) according to theprocedure in Example 1C. The product was purified by flashchromatography on silica (eluant EtOAc); yield 0.020 g (19%).

[0366] M.S.: calc m/e=450.19; found [M+H]⁺=451.2.

Example 25

[0367]5-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-1-oxo-1λ⁴-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0368] 25A.5-(4-Cyano-3-methylbenzoyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0369] The carboxylic acid from Example C (0.27 g; 1.68 mmol) wasreacted with 2,3,4,5-tetrahydro-1,5-benzothiazepine (0.28 g, 1.70 mmol)according to the procedure in Example 1A. The product was purified byflash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield0.43 g (84%).

[0370] 25B.5-(4-Aminomethyl-3-methylbenzoyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0371] The cyanobenzoyl benzothiazepine from Example 25A (0.43 g, 1.40mmol) was hydrogenated according to the procedure in Example 1B. Theproduct was isolated as the free base; yield 0.10 g (29%).

[0372] 25C.5-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0373] The amine from Example 25B (0.10 g, 0.32 mmol) was reacted with2,6-difluorophenylisocyanate (0.061 g, 0.39 mmol) according to theprocedure in Example 1C. The product was purified by trituration withdiethyl ether to give a white solid; yield 0.112 g (75%).

[0374] 25D.5-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-1-oxo-1λ⁴-2,3,4,5-tetrahydro-1,5-benzothiazepine

[0375] To a suspension of the thiazepine from Example 25C (0.15 g, 0.33mmol) in methanol (40 ml), dichloromethane (10 ml) and water (10 ml) wasadded sodium periodate (0.21 g, 0.99 mmol). The mixture was stirred atroom temperature for 70 h and then filtered. The filtrate was evaporatedin vacuo and the residue was purified by flash chromatography on silica(eluant EtOAc); yield 0.013 g (8%).

[0376] M.S.: calc m/e=483.14; found [M+H]⁺=484.1.

Example 26

[0377]4-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

[0378] 26A.4-(4-Cyano-3-methylbenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

[0379] The carboxylic acid from Example C (0.50 g, 3.10 mmol) wasreacted with 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (0.45 g, 2.95mmol) according to the procedure in Example 1A. The product was purifiedby recrystallisation from EtOAc:pet. ether; yield 0.48 g (55%).

[0380] 26B.4-(4-Aminomethyl-3-methylbenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

[0381] The nitrile from Example 26A (0.48 g, 1.60 mmol) was reducedaccording to the procedure in Example 16C; yield 0.169 (33%).

[0382] 26C.4-(4-[3-(2,6-Difluorophenyl)ureidomethyl]-3-methylbenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

[0383] The amine from Example 26B (0.05 g, 0.18 mmol) was reacted with2,6difluorophenylisocyanate (0.027 g, 0.18 mmol) according to theprocedure in Example 1C. The product was purified by tituration withdiethyl ether to give a white solid; yield 0.052 g (67%).

[0384] M.S.: calc m/e=455.15 found [M+H]⁺=456.1.

Example 27

[0385]4-(3-Methyl-4-[3-(2,3,5,6-tetrafluorophenyl)ureidomethyl]benzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

[0386] The amine from Example 26B (0.062 g, 0.206 mmol) was reacted with2,3,5,6-tetrafluorophenylisocyanate (0.079 g, 0.413 mmol, prepared fromthe aniline according to the procedure of Kurita. K, et al., J. Org.Chem., 41, 1976, p2070.) according to the procedure in Example 1C. Theproduct was purified by flash chromatography on silica (eluantEtOAc:pet. ether 50:50); yield 0.045 g (44%).

[0387] M.S.: calc m/e=491.13 found [M+H]⁺=492.1.

Example 28

[0388]1-(4-[N-(4-Methoxy-4-oxobutanoyl)aminomethyl]-3-methylbenzoyl-2,3,4,5-tetrahydro-1H-1-benzazepine

[0389] 28A.1-(4-Cyano-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0390] To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (0.80 g,5.44 mmol) in dichloromethane (40 ml) were added 4-cyano-3-methylbenzoicacid from example C (0.96 g, 5.95 mmol), triethylamine (0.76 g, 5.44mmol), 4-(dimethylamino)pyridine (0.66 g, 5.44 mmol) and WSCDI (2.17 g,10.88 mmol). The mixture was stirred at reflux for 18 h, cooled andevaporated in vacuo. The residue was partitioned between EtOAc and 1MKHSO₄. The organic layer was washed with saturated sodium bicarbonatesolution and brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica (eluantEtOAc:pet. ether 30:70); yield 1.10 g (70%).

[0391] 28B.1-(4-[Aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepinehydrochloride

[0392] To a degassed solution of the cyanobenzoyl benzazepine fromExample 28A (1.10 g, 3.79 mmol) in methanol (40 ml) were addedconcentrated hydrochloric acid (0.98 ml, 11.3 mmol) and 10%palladium-on-carbon (0.80 g). Hydrogen gas was bubbled through themixture for 5 h at room temperature. The catalyst was removed byfiltration through a pad of celit and the filtrate was evaporated invacuo to give the product as the HCl salt; yield 1.23 g (98%).

[0393] 28C.1-(4-[N-(4-Methoxy-4-oxobutanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0394] To a solution of the amine from Example 28B (0.10 g, 0.30 mmol)in dichioromethane (10 ml) were added triethylamine (0.061 ml, 0.90mmol) and 3-carbomethoxy propionyl chloride (0.046 g, 0.30 mmol). Themixture was stirred at room temperature for 18 h and then washed with 1MKHSO₄ (3 times), water and brine, dried over Na₂SO₄, and concentrated invacuo to give a white solid; yield 0.10 g (81%).

[0395] M.S.: calc m/e=408; found [M+H]⁺=409.

Example 29

[0396]1-(4-[N-(2-Methoxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0397] The amine hydrochloride from Example 28B (0.10 g, 0.30 mmol) wasreacted with methyl oxalyl chloride (0.037 g, 0.30 mmol) according tothe procedure in Example 28C to give a white solid; yield 0.085 g (76%).

[0398] M.S.: calc m/e=380; found [M+H]⁺=381.

Example 30

[0399]1-(4-[N-(2-Hydroxy-2-oxoethanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1benzazepine

[0400] To a solution of the methyl ester from Example 29 (0.045 g, 0.118mmol) in THF (10 ml) and water (5 ml) was added lithium hydroxidemonohydrate (0.010 g, 0.23 mmol). The mixture was stirred at roomtemperature for 2 h, acidified to pH1 by addition of 1M HCl andextracted with EtOAc (3 times). The combined organic extracts werewashed with brine, dried over Na₂SO₄, and concentrated in vacuo to givea white solid; yield 0.034 g (76%).

[0401] M.S.: calc m/e=366; found [M+H]⁺=367.

Example 31

[0402]1-(4-[N-(5-Methoxy-5-oxopentanoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0403] The amine hydrochloride from Example 28B (0.10 g, 0.30 mmol) wasreacted with methyl 4-(chloroformyl) butyrate (0.050 g, 0.30 mmol)according to the procedure in Example 1C to give a white solid; yield0.061 g (48%).

[0404] M.S.: calc m/e=422; found [M+H]⁺=423.

Example 32

[0405]1-(4-[N-(2-Ethoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0406] To a solution of the amine from Example 28B (0.10 g, 0.30 mmol)in dichloromethane (10 ml) were added triethylamine (0.061 ml, 0.90mmol) and ethyl isocyanatoacetate (0.059 g, 0.45 mmol). The mixture wasstirred at room temperature for 18 h and then washed with 1M KHSO₄ (3times), water and brine, dried over Na₂SO₄, and concentrated in vacuo togive a white,solid; yield 0.10 g (81%).

[0407] M.S.: calc m/e=423; found [M+H]⁺=424.

Example 33

[0408]1-(4-[N-(Carboxymethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0409] To a solution of the ethyl ester from Example 32 (0.050 g, 0.10mmol) in THF (20 ml) and water (5 ml) was added lithium hydroxidemonohydrate (0.020 g, 0.45 mmol). The mixture was stirred at roomtemperature for 4 h. The mixture was concentrated in vaicuo and theresidue diluted with water then washed with diethyl ether. The aqueouslayer was acidified to pH 1 by addition of 1M HCl and extracted withEtOAc (3 times). The combined organic extracts were washed with brine,dried over Na₂SO₄, and concentrated in vacuo to give a white solid;yield 0.046 g (99%).

[0410] M.S.: calc m/e=395; found [M+H]⁺=396.

Example 34

[0411]1-(4-[N-(2-Methylamino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0412] To a solution of the carboxylic acid from Example 33 (0.10 g,0.25 mmol) in dichloromethane (25 ml) was added DIEA (0.221 ml, 1.26mmol) and PyBroP (0.129 g, 0.278 mmol). The mixture was stirred at roomtemperature for 10 min and then methylamine hydrochloride (0.085 g, 1.26mmol) was added. Stirring was continued for a further 3 h. The mixturewas then washed with 1M KHSO₄ (3 times), saturated sodium bicarbonatesolution (3 times) and brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by flash chromatography on silica(eluant dichloromethane:methanol 96:4) to give a white solid; yield0.018 g (17%).

[0413] M.S.: calc m/e=408; found [M+H]⁺=409.

Example 35

[0414]1-(4-[N-(2-Dimethylamino-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0415] The carboxylic acid from Example 33 (0.07 g, 0.18 mmol) wasreacted with dimethylamine hydrochloride (0.072 g, 0.88 mmol) accordingto the procedure in Example 7. The product was purified by flashchromatography on silica (eluant chloroform:methanol:acetic acid 98:1:1)to give a white solid; yield 0.08 g (11%).

[0416] M.S.: calc m/e=422; found [M+H]⁺=423.

Example 36

[0417]1-(4-[N-(2-Methoxy-2-oxoethylcarbamoyl)aminomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0418] To a solution of the carboxylic acid from Example 33 (0.080 g,0.20 mmol) under a nitrogen atmosphere in dichloromethane (25 ml) at 0°C. were added DMF (20 □l) and oxalyl chloride (31 mg, 0.24 mmol). Themixture was stirred at 0° C. to room temperature for 2 h and thenconcentrated in vacuo. The residue was dissolved in methanol (4 ml) anddichloromethane (16 ml) and the mixture stirred at room temperature for16 h. The mixture was then washed with 1M KHSO₄ (3 times), saturatedsodium bicarbonate solution (3 times) and brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash chromatographyon silica (eluant dichloromethane:methanol 96:4) to give a white solid;yield 0.049 g (60%).

[0419] M.S.: calc m/e=409; found [M+H]⁺=410.

Example 37

[0420] 1-(4-[N-(2-Amino-2-oxoethylcarbamoyl)aminmethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine

[0421] To a solution of the carboxylic acid from Example 33 (0.10 g,0.25 mmol) in dichloromethane (20 ml) were-added hydroxybenzotrazole (34mg, 0.25 mmol) and WSCDI (51 mg, 0.25 mmol). The mixture was stirred atroom temperature for 10 min. Ammonia 880 (0.5 ml) was then added andstirring continued for a further 16 h. The mixture was concentrated invacuo and the residue purified by flash chromatography on silica (eluantethyl acetate) to give a white solid; yield 0.008 g (8%).

[0422] M.S.: calc m/e=394; found [M+H]⁺=395.

Example 38

[0423]4-(4-[N-(4-Methoxy-4-oxobutanoyl)aminomethyl]-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

[0424] 38A.4-(4-[N-(tert-Butyloxycarbonyl)aminomethyl]-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepinehydrochloride

[0425] The carboxylic acid from Example A2 (0.60 g, 2.10 mmol) wasreacted with 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine (0.28 g, 1.80mmol) according to the procedure in example 28A. The product waspurified by flash chromatography on silica (eluant EtOAc:pet. ether40:60) to give a yellow solid.

[0426] 38B.4-(4-[Aminomethyl]-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepinehydrochloride

[0427] The BOC amine from Example 38A was dissolved in 4N HCl/dioxan (30ml). The mixture was stirred at room temperature for 40 min thenconcentrated in vacuo to leave a tan solid; yield 0.41 g (63%, for 2steps). 38C.4-(4-[N-(4-Methoxy-4-oxobutanoyl)aminomethyl]-3-chlorobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine

[0428] To a solution of the amine from Example 38B (0.032 g, 0.08 mmol)in dichloromethane (10 ml) were added triethylamine (0.025 ml, 0.18mmol) and 3-carbomethoxypropionyl chloride (0.014 g, 0.08 mmol). Themixture was stirred at room temperature for 18 h and then washed with 1MKHSO₄ (3 times), water and brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by flash chromatography on silica(eluant EtOAc:pet. ether 50:50-90:10); yield 0.022 g (56%).

[0429] M.S.: calc m/e=434; found [M+H]⁺³⁵Cl=435.

Example 39

[0430]1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide

[0431] 39A.2-Methyl-4-((2,3,4,5-tetrahydro-1H-benzo[b]azepine)-1-carbonyl)-benzonitrile.

[0432] To a solution of 2,3,4,5-tetrahydro-1H-benzo[b]azepine (0.80 g,5.44 mmol) in dichloromethane (50 ml) were added 4-cyano-3-methylbenzoicacid (0.96 g, 5.95 mmol), triethylamine (0.60 g, 5.95 mmol),4-(dimethylamino)pyridine (0.73 g, 5.95 mmol) and WSCDI (1.24 g, 6.48mmol). The mixture was stirred at reflux for 18 h, cooled and evaporatedin vacuo. The residue was partitioned between EtOAc and 1M KHSO₄. Theorganic layer was washed with saturated sodium bicarbonate solution andbrine, dried over MgSO₄, and concentrated in vacuo. The crude materialwas purified by flash chromatography on silica (eluant EtOAc:pet. ether30:70); yield 1.10 g (70%).

[0433] 39B.1-(4-(Aminomethyl)-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepinehydrochloride.

[0434] To a degassed solution of the cyanobenzazepine of Example 39A(1.10 g, 3.79 mmol) in methanol (50 ml) were added concentratedhydrochloric acid (0.98 ml, 11.3 mmol) and 10% palladium on carbon (0.80g). Hydrogen gas was bubbled through the mixture for 5 h at roomtemperature. The catalyst was removed by filtering through a pad ofcelite and the filtrate was evaporated; yield 1.23 g (98%).

[0435] 39C.1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide

[0436] To a solution of the amine of Example 39B (0.10 g, 0.302 mmol) inDMF (10 ml), under a nitrogen atmosphere, were addedN,N-diisopropylethylamine (43 mg, 0.332 mmol) and carbonyl diimidazole(0.074 g, 0.453 mmol). The mixture was stirred at room temperature for40 minutes. A solution of proline-N,N-dimethylamide (0.107 g, 0.756mmol) in DMF (1 ml) was added. The mixture was stirred at roomtemperature for a further 16 hr. The solvent was removed in vacuo andthe crude material was purified by flash chromatography on silica(eluant methanol:dichloromethane 5:95); yield 0.115 g (82%).

[0437] M.S.: calc m/e=462.26; found [M+H]⁺=463.2

Example 40

[0438](4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide

[0439] 40A. L-trans-4-Hydroxyproline-N,N-dimethylamide hydrochloride

[0440] To a solution of BOC-hydroxyproline (2.99 g, 13.89 mmol) indichloromethane (100 ml) were added N,N-diisopropylethylamine (3.7 ml,21.24 mmol), 4-(dimethylamino)pyridine (1.74 g, 14.24 mmol),dimethylamine hydrochloride (1.72 g, 21.09 mmol) and WSCDI (3.17 g,16.68 mmol). The mixture was stirred at room temperature for 30 h. Themixture was diluted with dichloromethane (100 ml) and washed with 0.3MKHSO₄, saturated sodium bicarbonate solution and brine, dried overMgSO₄, and concentrated in vacuo to give a colourless gum. This crudematerial was taken up in 4N HCl/dioxan (50 ml) and stirred at roomtemperature for 1 hr and then concentrat d in vacuo. The residue wasazeotroped with toluene and diethyl ether to give a white solid; yield0.45 g (17%).

[0441] 40B.(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl-L-proline-N,N-dimethylamide.

[0442] The amine of Example 39B (0.10 g, 0.302 mmol) was reacted withthe amine of Example 40A (0.153 mg, 0.785 mmol) following the method ofExample 39C. The product was purified by flash chromatography on silica(eluant chloroform:methanol:acetic acid 95:4:1); yield 0.95 g (66%).

[0443] M.S.: calc m/e=478.26; found [M+H]⁺=479.2

[0444] Following the above methods, the following compounds were alsoprepared. TABLE A Examples 41-44

Ex. Ar W Z M + H⁺ 41 Ph N CH═CH 465.4 42 Ph CH S 470.2 43 4-Me—Ph CHCH═CH 478.1 44 2-Me—Ph CH CH═CH 478.1

[0445] TABLE B Examples 45-55

Ex. Ar R¹ R² R³⁴ A¹⁶ V M + H⁺ 45 2,6-F₂—Ph H H H NCH₂Ph O 527.4 462,6-F₂—Ph H H H S O 454 47 1-Nap H H Cl CH₂ O 484 48 Ph H H Cl CH₂ O 43449 3-Pyr H H Me CH₂ S 431.1 50 2,6-F₂—Ph MeO H H CH₂ O 466 51 2,6-F₂—PhH CH:CH═CH:CH CH₂ O 486 52 2,6-F₂—Ph H H Me N(CH₂)₂NMe₂ O 522.3 532,6-F₂—Ph Cl H Cl CH₂ O 504.1 54 2,6-F₂—Ph H H Me SO₂ O 500.2 552,6-F₂—Ph H H HMe NCH₂CO₂H O 509.2

[0446] TABLE C Examples 56-57

Ex. G¹ M + H⁺ 56

488.3 57

517.1

[0447] TABLE D Examples 58-61

Ex. G¹ R⁸ M + H⁺ 58

OEt 439 59

NMe₂ 473.3 60

NMe₂ 461.1 61

NMe₂ 476

[0448] TABLE E Examples 62-70

Ex. f R² R³ R⁸ M + H⁺ 62 1 H Me

463 63 1 H Me

449.2 64 0 H Me OEt 410 65 1 Me H OEt 424 66 1 H Me OiPr 438 67 1 H MeOtBu 452 68 1 H Cl NMe₂ 443 69 2 H Me OEt 438 70 2 H Me OH 410

[0449] TABLE F Examples 71-77

Ex. A¹⁶ f R² R³ R⁸ M + H⁺ 71 O 2 H H OMe 397 72 CH₂ 1 H Me OMe 415 73CH₂ 1 H Mde OEt 409 74 CH₂ 1 H Me OH 381 75 CH₂ 2 H Me OH 395 76 CH₂ 3 HMe OH 409 77 CH₂ 1 Me H OMe 395

[0450] TABLE G Examples 78-90

Ex. G¹ R³ M + H⁺ 78

Me 502 79

OMe 479.2 80

Et 477.3 81

Me 479.2 82

Me 518.0 83

Me 532.2 84

Me 517.2 85

Me 513.7 86

Me 527.0 87

Me 514.6 88

Me 516.1 89

Me 515.0 90

Me 500.7

[0451] TABLE H Examples 91-106

Ex. G¹ E¹ E² M + H⁺ 91

H OAc 521.0 92

═O 477.3 93

H OBn 638.2 94

Br H 541.1 95

F F 499.2 96

H OBn 619.2 97

H N₃ 504.3 98

H O-tBu 535.3 99

H OH 517.6 100

H OH 546.3 101

H OH 547.9 102

H OMe 548.2 103

H OMe 562.1 104

H Cl 566.2 105

H NHBn 568 106

OCH₂CH₂O 558.3

[0452] TABLE I Examples 107-124

Ex. G¹ R³ F¹ F² L M + H⁺ 107

Me ═O NMe₂ 493.5 108

Me ═O NMe₂ 530.3 109

Me ═O NMe₂ 543.4 110

Me ═O NMe₂ 532.4 111

Me ═O NMe₂ 544.3 112

Me ═O NMe₂ 536.4 113

Me ═O NMe₂ 494.5 114

Cl ═O NMe₂ 515.2 115

Cl ═O NMe₂ 551.5 116

Me ═O NMeEt 558.3 117

Me ═O

570.3 118

Me ═S NMe₂ 546.2 119

Cl ═S NMe₂ 535.1 120

Cl ═S NMe₂ 585.1 121

Me ═O NMe₂ 590.2 122

Me ═O NMe₂ 548.2 123

Me ═O NMe₂ 494.3 124

Me ═O NMe₂ 522.4

[0453] TABLE J Examples 125-153

Ex. E¹ E² F¹ F² L M + H⁺ 125 H H H H OMe R 436.4 126 H H H H OMe S 436.2127 H H ═O NMeEt R 477.2 128 H OPh ═O OMe R 542.3 129 H OPh ═O OH RS528.3 130 H OPh ═O NMe₂ RS 555.3 131 H F ═O OH R 454.4 132 OMe OMe ═OOMe R 510.3 133 OMe OMe ═O OH R 496.2 134 H H ═O OtBu R 492.5 135 H H ═OOH R 436.3 136 H OH ═O OMe R 466.0 137 H OH ═O OEt R 480.2 138 H H ═SNMe₂ R 479.2 139 H OMe ═O OMe R 480.2 140 H H ═O OiPr R 478.2 141 H OH═O OH R 452.1 142 H OBn ═O OiPr R 584.2 143 H OH ═O OiPr R 494.1 144 HOBn ═O NMe₂ R 569.2 145 H OMe ═O OH R 466.2 146 H OEt ═O NMe₂ R 507.3147 H Cl ═O OMe R 484.1 148 H Cl ═O OH R 470.1 149 H Cl ═O NMe₂ R 497.2150 Cl H ═O NMe₂ R 497.2 151 H F ═O OMe R 468.3 152 H F ═O NMe₂ R 481.3153 OMe OMe ═O NMe₂ R 523.3

[0454] TABLE K Examples 154-159

Ex. R² R³ E² F¹ F² M + H⁺ 154 H Cl H ═O 483.4 155 Me H H ═O 463.2 156 ClH H ═O 483.1 157 H Cl H ═S 499.2 158 H Cl OBn ═O 589.2 159 H Cl OH ═O499.2

[0455] TABLE L Examples 160-164

Ex. R² E² M + H⁺ 160 Cl H 489.1 161 Me H 469.2 162 Me OH 485.0 163 ClOMe 519.3 164 Me OMe 499.3

[0456] TABLE M Examples 165-170

Ex. R⁴ E² F¹ F² V M + H⁺ 165 H H ═O S 479.4 166 H OH ═O S 495.0 167 H H═S S 495.1 168 Me H ═O O 477.2 169 H OBn ═O S 585.2 170 H OBn ═S O 585.0

[0457] TABLE N Examples 171-177

Ex. E¹ E² F¹ F² L M + H⁺ 171 H H ═S NMe₂ 516.2 172 H OBn ═O NMe₂ 606.3173 H OH ═O NMe₂ 507.3 174 OMe OMe ═O OMe 547.3 175 —OCH₂CH₂O— ═O OMe545.3 176 —OCH₂CH₂O— ═O NMe₂ 558.3 177 —SCH₂CH₂S— ═O NMe₂ 590.2

[0458] TABLE O Examples 178-182

Ex. E¹ E² F¹ F² L M + H⁺ 178 H OH ═O NMe₂ 516.1 179 H H ═S NMe₂ 516.2180 H OMe ═O NMe₂ 530.4 181 —OCH₂CH₂O— ═O OMe 545.3 182 —OCH₂CH₂O— ═O OH531.3

[0459] TABLE P Examples 183-190

Ex. A¹⁰ R³ E² F¹ F² M + H⁺ 183 O Me H ═O 519.3 184 NMe Me H ═O 532.33185 NMe Me OH ═O 548.1 186 NMe Me OMe ═O 562.3 187 O Me OMe ═O 549.2 188NMe Me OMe ═S 578.2 189 O Cl OMe ═O 569.1 190 O Me OMe ═S 565.2

[0460] TABLE Q Representative NMR data Ex. No ¹H NMR(CDCl₃) 28 δ1.40-1.60(1H, m), 1.84-2.20(3H, m), 2.15(3H, s), 2.40-2.54(2H, m),2.58-2.92(4H, m), 2.94-3.10(1H, m), 3.65(3H, s), 4.30(2H, d, J=5.6Hz),4.99(1H, d, J=12.9Hz), 5.90(1H, s), 6.62(1H, d, J=7.9Hz) 6.78-6.96(3H,m), 7.00-7.16(2H, m), 7.21(1H, m)ppm 29 δ 1.48-1.70(1H, m),1.96-2.16(3H, m), 2.26(3H, s), 2.78-3.18(3H, m), 3.98(3H, s), 4.50(2H,d, J=6.8Hz), 5.08(1H, d, J=12.7Hz), 6.72(1H, d, 7.6Hz), 6.88-7.06(3H,m), 7.18(1H, t, J=7.6Hz), 7.22-7.36(2H, m)ppm 30 δ 1.40-1.62(1H, m),1.84-2.24(3H, s), 2.17(3H, s), 2.70-3.10(3H, m), 4.40(2H, d, J=5.9Hz),4.99(1H, d, J=12.9Hz), 6.63(1H, d, J=7.6Hz), 6.80-6.98(3H, m),7.02-7.28(3H, m), 7.38(1H, brs)ppm 31 δ 1.42-1.62(1H, m), 1.84-2.28(8H,m), 2.30-2.50(4H, m), 2.70-2.94(2H, m), 2.96-3.12(1H, m), 3.65(3H, s),4.31(2H, d, J=5.3Hz), 4.99(1H, d, J=13.9Hz), 5.75(1H, brs), 6.63(1H, d,J=7.6Hz), 6.78-6.98(3H, m), 7.02-7.16(2H, m), 7.21(1H, d, J=6.6Hz)ppm 32δ 1.18(3H, t, J=7.3Hz), 1.38-1.55(1H, m), 1.80-2.10(3H, m), 1.95(3H, s),2.60-2.98(3H, m), 3.84(2H, s), 4.04(2H, s), 4.07(2H, q, J=7.3Hz),4.87-4.92(1H, m), 5.73(2H, brs), 6.50(1H, d, J=7.3Hz), 6.63-6.97(5H, m),7.11(1H, d, J=7.3Hz)ppm 33 δ 1.30-1.50(1H, m), 1.75-2.05(3H, m),1.94(3H, s), 2.60-2.98(3H, m), 3.59(2H, brs), 4.01(2H, brs),4.80-4.85(1H, m), 6.05(2H, brs), 6.53(1H, d, J=7.2Hz), 6.75-6.99(5H, m),7.11(1H, d, J=7.2Hz)ppm. 34 δ 1.40-1.60(1H, m), 1.80-2.00(2H, m),2.00-2.20(3H, s), 2.60(3H, d, J=4.0Hz), 2.65-3.05(3H, m), 3.60(2H, d,J=4.0Hz), 4.15(2H, d, J=4.0Hz), 4.90-5.00(1H, m), 6.10-6.30(2H, m),6.60(1H, d, J=8.0Hz), 6.70-7.20 (8H, m)ppm 35 δ 1.39-1.50(1H, m),1.86-2.10(3H, m), 2.07(3H, s), 2.57(3H, s), 2.60-3.00(3H, m), 2.85(3H,s), 3.95(2H, d, J=4.0Hz), 4.16(2H, d, J=5.6Hz), 4.90-5.00(1H, m),5.74(1H, brs), 6.11(1H, brs), 6.54(1H, d, J=7.6Hz), 6.78-7.18(6H, m)ppm36 δ 1.38-1.50(1H, m), 1.80-2.00(3H, m), 2.00(3H, s), 2.60-3.00(3H, m),3.64(3H, s), 3.90(2H, s), 4.10(2H, s), 4.85-4.95(1H, m), 6.52(1H, d,J=7.2Hz), 6.67-7.02(7H, m), 7.13(1H, d, J=6.2Hz)ppm 37 δ 1.40-1.76(2H,m), 1.84-2.16(2H, m), 2.29(3H, s), 2.66-3.10(3H, s), 3.95(2H, s),4.56(2H, s), 4.99(1H, d, J=13.9Hz), 5.59(1H, brs), 6.63 (1H, d,J=7.9Hz), 6.80-6.98(3H, m), 7.00-7.12(2H, m), 7.20(1H, d, J=7.3Hz)ppm 38δ 1.70-1.86(3H, m), 1.96-2.08(2H, m), 2.44-2.56(2H, m), 2.60-2.72(2H,m), 2.86-2.98(2H, m), 3.67(3H, s), 3.85(1H, brs), 4.44(2H, d, J=5.9Hz),6.18(1H, d, J=5.3Hz), 6.28(1H, brs), 6.68(1H, d, J=5.3Hz), 7.03(1H, d,J=7.6Hz), 7.15(1H, d, J=7.6Hz)ppm 39 δ 1.35-1.55(1H, m), 1.74-2.10(3H,m), 2.11(3H, s), 2.17-2.35(1H, m), 2.60-2.82(2H, m), 2.86(3H, s),2.90-3.14(2H, m), 3.05(3H, s), 3.26(1H, dd, J=14.9&7.2Hz), 3.40-3.53(1H,m), 3.64-3.84(1H, m), 4.03-4.19(1H, m), 4.29-4.42(1H, m), 4.55-4.68(1H,m), 4.74-4.81(1H, m), 4.85-4.98(1H, m), 6.58(1H, d, J=7.7Hz),6.75-6.89(2H, m), 6.91-7.06(3H, m), 7.16(1H, d, J=6.5Hz), 7.93-8.03(1H,m)ppm 40 δ 1.65-1.80(2H, m), 1.85-2.00(3H, m), 2.05-2.25(1H, m),2.10(3H, s), 2.80-3.10(3H, m), 2.85(3H, s), 3.00(3H, s), 3.40-3.30(1H,m), 3.45-3.55(1H, m), 3.65-3.95(1H, m), 4.00-4.10(1H, m), 4.30-4.55(1H,m), 4.91(1H, t, J=7.7Hz), 5.15-5.30(1H, m), 6.10-6.20(1H, m),6.55-6.65(1H, m), 6.85-7.50(5H, m)ppm 66 δ 1.17(6H, d, J=6.3Hz),1.20-1.24(1H, m), 1.80-2.10(3H, m), 2.00(3H, s), 2.60-3.00(3H, m),3.85(2H, d, J=5.3Hz), 4.10(2H, d, J=4.9Hz), 4.82-4.85(1H, m), 4.96(1H,sept, J=6.2Hz), 5.33(1H, t, J=5.2Hz), 5.43(1H, t, J=4.9Hz), 6.52(1H, d,J=7.6Hz)ppm 67 δ 1.38-1.42(1H, m), 1.38(9H, s), 1.78-2.10(3H, m),1.97(3H, s), 2.60-3.00(3H, m), 3.78(2H, s), 4.07(2H, s), 4.89-4.94(1H,m), 5.50(2H, brs), 6.51(1H, d, J=7.9Hz), 6.64-6.98(5H, m), 7.12(1H, d,J=7.7Hz)ppm 68 δ 1.38-1.50(1H, m), 1.80-2.06(3H, m), 2.60-3.00(3H, m),2.70(3H, s), 2.87(3H, s), 3.96(2H, d, J=4.0Hz), 4.27(2H, d, J=6.0Hz),4.85-4.95(1H, m), 5.98(1H, t, J=6.0Hz), 6.14(1H, t, J=4.0Hz), 6.55(1H,d, J=7.6Hz), 6.80-7.16(6H, m)ppm 69 δ 1.25(3H, t, J=7.0Hz),1.40-1.60(1H, m), 1.85-2.20(3H, m), 2.04(3H, s), 2.45(2H, t, J=6.27Hz),2.65-3.10(3H, m), 3.30-3.50(2H, m), 4.00-4.20(4H, m), 4.90-5.00(1H, m),5.50-5.70(2H, m), 6.50-7.20(7H, m)ppm 70 δ 1.20-1.45(1H, m),1.65-2.05(3H, m), 1.95(3H, s), 2.05-2.25(2H, m), 2.50-3.00(3H, m),3.00-3.20(2H, m), 3.85-4.05(2H, m), 4.65-4.90(1H, m), 5.80-6.20(1H,brs), 6.40-7.20(9H, m)ppm

Example 191

[0461] Determination of V₂r Ceptor Agonist Activity in Vitro

[0462] Agonist activity was determined for all compounds and is reportedas an EC₅₀ value, being that concentration of compound necessary tocause a half-maximal cellular activation. All the compounds had EC₅₀values of 10 μM or less, and typical results are listed in Table R.TABLE R EC₅₀ values for typical compounds Compound of Example EC₅₀ (nM)1 39 2 160 3 300 4 300 5 150 6 47 7 24 8 220 9 50 10 4 11 21 12 50 13 3814 240 15 44 16 16 17 16 18 17 19 40 20 17 21 180 22 1000 23 40 24 92 25280 26 10 27 23

Example 192

[0463] Determination of Antidiuretic Activity in Vivo

[0464] The Brattleboro rat is a recognised model for vasopressindeficiency (for a review see FD Grant, “Genetic models of vasopressindeficiency”, Exp. Physiol. 85, 203S-209S, 2000). The animals do notsecrete vasopressin and consequently produce large volumes of diluteurine. Compounds of the invention were administered to Brattleboro rats(0.1-10 mg/kg p.o. in methylcellulose. Urine was callected hourly andvolumes were compared with control animals. Animals had free access tofood and water throughout the experiment. Representative results aregiven in Table S. Results for Desmopressin are given for comparison.TABLE S Antidiuretic activity % inhibition of urine output Compound ofExample Dose (at 1 hour) 32 1 mg/kg 74 33 1 mg/kg 38 35 1 mg/kg 45-82 391 mg/kg 82 62 1 mg/kg 58 88 1 mg/kg 60 103  1 mg/kg 63 107  1 mg/kg 84119  1 mg/kg 68 163  1 mg/kg 90 Desmopressin 0.1 mg/kg   37 1 mg/kg 100 10 mg/kg  100 

Example 193

[0465] Pharmaceutical Composition for Tablet

[0466] Tablets containing 100 mg of the compound of Example 39 as theactive agent are prepared from the following: Compound of Example 39200.0 g Corn starch  71.0 g Hydroxypropylcellulose  18.0 gCarboxymethylcellulose calcium  13.0 g Magnesium stearate  3.0 g Lactose195.0 g Total 500.0 g

[0467] The materials are blended and then pressed to give 2000 tabletsof 250 mg, each containing 100 mg of the compound of Example 39.

[0468] The foregoing Examples demonstrate that compounds within thescope of the invention are readily prepared using standard chemicaltechniques, and that these compounds have the biological properties thatwould be expected of V₂ receptor agonists. In particular, the compoundsare potent antidiuretic in an animal model of vasopressin deficiency.Thus it is clear that they may be useful in the treatment of humandiseases that are currently treatable with Desmopressin, such as centraldiabetes insipidus, nocturnal enuresis and nocturia. It has further beensuggested that antidiuretics such as Desmopressin may be useful incertain types of urinary incontinence. These arguments would also extendto the compounds of the present invention.

[0469] Desmopressin is also used in the treatment of certain coagulationdisorders. There is good evidence to suggest that this action is alsomediated through the V₂ receptor (see for example J E Kaufmann et al.,“Vasopressin-induced von Willebrand factor secretion from endothelialcells involves V₂ receptors and CAMP”, J. Clin. Invest. 106, 107-116,2000; A Bernat et al., “V₂ receptor antagonism of DDAVP-induced releaseof hemostasis factors in conscious dogs”, J. Pharmacol. Exp. Ther. 282,597-602, 1997), and hence it would be expected that the compounds of thepresent invention should be useful pro-coagulants.

The scope of the present invention is further defined in the followingclaims.
 1. A compound according to general formula 1 or 2, or a tautomeror a pharmaceutically acceptable salt thereof,

wherein: W is either N or C—R⁴; R¹-R⁴ are independently selected from H,F, Cl, Br, alkyl, CF₃, phenyl, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂,NO₂ and CN, or R² and R³ together can be —CH═CH—CH═CH—; G¹ is a bicyclicor tricyclic fused azepine derivative selected from general formulae 3to 8,

 in which A¹, A⁴, A⁷ and A¹⁰ are each independently selected from CH₂, Oand NR⁵; A², A³, A⁹, A¹¹, A¹³, A¹⁴ and A¹⁵ are each independentlyselected from CH and N; either A⁵ is a covalent bond and A⁶ is S, or A⁵is N═CH and A⁶ is a covalent bond; A⁸ and A¹² are each independentlyselected from NH, NCH₃ and S; A¹⁶ and A¹⁷ are both CH₂, or one of A¹⁶and A¹⁷ is CH₂ and the other is selected from CH(OH), CF₂, O, SO_(a) andNR⁵; R⁵ is selected from H, alkyl, CO-alkyl and (CH₂)_(b)R⁶; R⁶ isselected from phenyl, pyridyl, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂,NO₂, CO₂H and CN; a is 0, 1 or 2; b is 1, 2, 3 or 4; Y is CH or N; Z isCH═CH or S; and G² is a group selected from general formulae 9 to 11,

 in which Ar is selected from phenyl, pyridyl, naphthyl and mono- orpolysubstituted phenyl or pyridyl wherein the substituents are selectedfrom F, Cl, Br, alkyl, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂, NO₂ andCN; D is a covalent bond or NH; E¹ and E² are both H, OMe or F, or oneof E¹ and E² is OH, O-alkyl, OBn, OPh, OAc, F, Cl, Br, N₃, NH₂, NHBn orNHAc and the other is H, or E¹ and E² together are ═O, —O(CH₂)_(g)O— or—S(CH₂)_(g)S—; F¹ and F² are both H, or together are ═O or ═S; L isselected from OH, O-alkyl, NH₂, NH-alkyl and NR⁹R¹⁰; R⁷ is selected fromH, alkyl, alkenyl and COR⁸; R⁸ is selected from OH, O-alkyl, NH₂,NH-alkyl, N(alkyl)₂, pyrrolidinyl and piperidinyl; R⁹ and R¹⁰ are bothalkyl, or together are —(CH₂)_(h)— or —(CH₂)₂O(CH₂)₂—; V is O, N—CN orS; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is 0, 1, 2, 3 or 4; g is 2or 3; and h is 3, 4 or 5, provided that d and e are not both
 0. 2. Acompound according to claim 1, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein the compound is a compound according togeneral formula
 1. 3. A compound according to claim 2, or a tautomer orpharmaceutically acceptable salt thereof, wherein W is C—R⁴.
 4. Acompound according to claim 3, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein at least one of R¹-R⁴ is not H.
 5. Acompound according to claim 4, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein one of R¹-R⁴is methyl, F or Cl and theothers are all H.
 6. A compound according to claim 1, or a tautomer orpharmaceutically acceptable salt thereof, wherein the compound is acompound according to general formula
 2. 7. A compound according to anypreceding claim, or a tautomer or pharmaceutically acceptable saltthereof, wherein G¹ is a group according to one of general formulae 3 to7.
 8. A compound according to claim 7, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein Y is CH.
 9. A compound according toclaim 8, or a tautomer or pharmaceutically acceptable salt thereof,wherein Z is —CH═CH—.
 10. A compound according to claim 8, or a tautomeror pharmaceutically acceptable salt thereof, wherein Z is S.
 11. Acompound according to claim 7, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein Y is N and Z is —CH═CH—.
 12. A compoundaccording to any of claims 7 to 11, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein G¹ is a group according to generalformula
 3. 13. A compound according to claim 12, or a tautomer orpharmaceutically acceptable salt thereof, wherein A¹ is CH₂ and A² andA³ are both CH.
 14. A compound according to any of claims 7 to 11, or atautomer or pharmaceutically acceptable salt thereof, wherein G¹ is agroup according to general formula
 6. 15. A compound according to claim14, or a tautomer or pharmaceutically acceptable salt thereof, whereinA¹¹ is CH and A¹² is S.
 16. A compound according to any of claims 1 to6, or a tautomer or pharmaceutically acceptable salt thereof, wherein G¹is a group according to general formula
 8. 17. A compound according toclaim 16, or a tautomer or pharmaceutically acceptable salt thereof,wherein A¹⁷ is CH₂.
 18. A compound according to either claim 16 or 17,or a tautomer or pharmaceutically acceptable salt thereof, wherein A¹⁶is CH₂.
 19. A compound according to any preceding claim, or a tautomeror pharmaceutically acceptable salt thereof, wherein G² is a groupaccording to general formula
 9. 20. A compound according to claim 19, ora tautomer or pharmaceutically acceptable salt thereof, wherein Ar ismono- or polysubstituted phenyl.
 21. A compound according to eitherclaim 19 or 20, or a tautomer or pharmaceutically acceptable saltthereof, wherein Ar is phenyl substituted with at least two halogenatoms selected from F and Cl.
 22. A compound according to any of claims19 to 21, or a tautomer or pharmaceutically acceptable salt thereof,wherein Ar is 2,6-difluorophenyl.
 23. A compound according to any ofclaims 1 to 18, or a tautomer or pharmaceutically acceptable saltthereof, wherein G² is a group according to general formula
 10. 24. Acompound according to claim 23, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein R⁷ is COR⁸.
 25. A compound according toclaim 24, or a tautomer or pharmaceutically acceptable salt thereof,wherein R⁸ is N(alkyl)₂.
 26. A compound according to any of claims 1 to18, or a tautomer or pharmaceutically acceptable salt thereof, whereinG² is a group according to general formula
 11. 27. A compound accordingto claim 26, or a tautomer or pharmaceutically acceptable salt thereof,wherein F¹ and F² together are ═O.
 28. A compound according to eitherclaim 26 or 27, or a tautomer or pharmaceutically acceptable saltthereof, wherein E¹ and E² are both H or one is H and the other isO-alkyl.
 29. A compound according to any of claims 26 to 28, or atautomer or pharmaceutically acceptable salt thereof, wherein one of E¹and E² is H and the other is O-alkyl, and the stereochemistry at theCE¹E² centre is of the R absolute configuration.
 30. A compoundaccording to any of claims 26 to 29, or a tautomer or pharmaceuticallyacceptable salt thereof, wherein the stereochemistry adjacent to thering nitrogen is of the S absolute configuration.
 31. A compoundaccording to claim 1, or a tautomer or pharmaceutically acceptable saltthereof, selected from1-(4-[3-(2-Chloro-6-fluorophenyl)ureidomethyl]-3-methylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine,1-(4-[3-(2,6-Difluorophenyl)ureidamethyl]-3-methylbenzoyl)-5-(3-pyridyl)methyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine,1-(3-Chloro-4-[3-(2-chloro-6-fluorophenyl)ureidomethyl]benzoyl)-5-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine,4-(3-Chloro-4-[3-(2,6-difluorophenyl)ureidomethyl]benzoyl-5,6,7,8-tetrahydrothieno[3,2-b]azepine,1-(3-Chloro-4-(3-(methyloxycarbonyl)propanoylaminomethyl)benzoyl)-2,3,4,5-tetrahydro-1-benzazepine,1-(2-Methyl-4-(5-(3-pyridylmethyl)-2,3,4,5-tetrahydro-1,5-benzodiazepin-1-ylcarbonyl)benzyl)-3-(methyloxycarbonylmethyl)urea,1-(2-Methyl-4-(2,3,4,5tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,(4R)-1-(3-Chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,(4R)-1-(2-Chloro-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,(4R)-4-Benzyloxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,(4R)-4-Methoxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,(4R)-4-Methoxy-1-(3-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide,(4R)-1-(2-Chloro-4-(5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-4-ylcarbonyl)benzyl-carbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,(4R)-1-(4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,(4R)-1-(2-Chloro-4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylamide,and(4R)-1-(4-(10,11-Dihydro-5H-pyrrolo[2,1-c](1,4)benzodiazepin-10-ylcarbonyl)-2-methyl-benzylcarbamoyl)-4-methoxy-L-proline-N,N-dimethylthioamide.32. A compound according to claim 1, or a tautomer or pharmaceuticallyacceptable salt thereof, selected from1-(2-Methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzylcarbamoyl)-L-proline-N,N-dimethylamide,and(4R)-4-Hydroxy-1-(2-methyl-4-(2,3,4,5-tetrahydro-1-benzazepin-1-ylcarbonyl)benzyl-carbamoyl)-L-proline-N,N-dimethylamide.33. A use for a compound according to any of claims 1 to 32 or apharmaceutically acceptable salt thereof, which use is as a component ofa pharmaceutical composition.
 34. A use for a compound according to anyof claims 1 to 32 or a pharmaceutically acceptable salt thereof, whichuse is as a therapeutic agent for the treatment of nocturnal enuresis,nocturia, polyuria resulting from central diabetes insipidus, urinaryincontinence or bleeding disorders.
 35. A pharmaceutical compositionwhich comprises, as an active agent, a compound according to any ofclaims 1 to
 32. 36. A pharmaceutical composition according to claim 35,which composition is to be used for the treatment of polyuria.
 37. Apharmaceutical composition according to claim 35, which composition isto be used for the control of urinary incontinence.
 38. A pharmaceuticalcomposition according to claim 37, which composition is for voidingpostponement.
 39. A pharmaceutical composition according to claim 35,which composition is to be used for the treatment of bleeding disorders.40. A method of treatment of nocturnal enuresis, nocturia and diabetesinsipidus, which method comprises the administration to a person in needof such treatment of an effective amount of a composition according toclaim
 35. 41. A method for the control of urinary incontinence, whichmethod comprises the administration to a person in need of suchtreatment of an effective amount of a composition according to claim 35.42. A method for the control of urinary incontinence according to claim41, wherein the treatment results in voiding postponement.
 43. A methodfor the treatment of bleeding disorders, which method comprises theadministration to a person in need of such treatment of an effectiveamount of a composition according to claim 35.